Esters of Short Chains Fatty Acids for Use in the Treatment of Immunogenic Disorders

ABSTRACT

The present invention relates to short chain fatty acids (SCFA) for use in transmucosal administration to a subject for the prevention, attenuation or treatment of a disease or disorder associated with a compromised Th1 immune response and/or an unwanted Th2 or Th2-like immune response by modulating a Th2 immune response towards a Th1 immune response, particularly for the treatment, prevention and/or amelioration of viral infections and as an adjuvant for promoting the efficiency of vaccines and/or prevention of allergic diseases or disorders.

The present invention relates to short chain fatty acids (SCFA) formodulating an immune response. In particular, compositions and methodsare provided for use in the treatment, prevention or attenuation ofviral infections and/or virus-induced exacerbations of allergy orautoimmunity. In a second aspect, compositions and methods are providedfor use in the prevention of development of a Th2 induced inflammatorycondition in a tissue or organ of a subject.

Inefficient or misdirected immune responses are responsible for a broadrange of human diseases and disorders. It is commonly accepted that aninappropriate Th1 cell driven immune response can be the reason forinsufficient virus clearing and the development of autoimmune andallergic diseases or disorders.

Furthermore, cytokine compositions play also an important role in thechronic inflammation of allergic diseases such as, for example, asthmaand play a critical role in orchestrating the allergic inflammatoryresponse. Of particular importance to allergic disease is the recentrecognition of the regulation of helper immune function by two lineagesof T helper cells, i.e., Th1 and Th2, by these cytokines. The Th2hypothesis of allergy considers atopy as a Th2-driven hypersensitivityreaction to allergens of complex genetic and environmental origins, inwhich the Th1 lineage, normally driven by IL-2, TNF, and IFN-γ isdeficient, and in which a predominant Th2 response is seen that ismediated by IL-4, IL-13, IL-5, and IL-10.

Literature shows that Th2 lymphocytes are presently considered the mainorchestrator of allergic airway inflammation underlying asthma.Functional analysis of the role of cytokines, largely based on in vivoanimal models, confirms this hypothesis. During T cell differentiationfrom naive T cells into Th1 and Th2 cells, the expression of IL-10 inTh1 cells slowly disappear, whereas Th2 cells produce more IL-10. Incontrast, Th2 cells secrete IL-4, IL-5, IL-9, IL-10, and IL-13, whichare involved in isotype switching of B cells as well as proliferationand differentiation into antibody-secreting plasma cells. Interleukin-4and IL-10 are also regulatory cytokines, antagonizing the activities ofTh1 cytokines. Thus, the nature, intensity and duration of a specificimmune response depend on the delicate balance between Th1 and Th2numbers or activities (or both).

In particular, IL-4 and IL-13 are involved in the isotype switch fromIgM to IgE, the antibody responsible for classic allergy and implicatedin the pathophysiology of allergic asthma. Excessive IL-4 production byTh2 cells has been associated with elevated IgE production and allergy.

Recent studies with gene knockout mice have demonstrated that T helper 2(Th2) cell-derived cytokines, including IL-4, IL-5, and IL-13, playimportant roles in causing allergic airway inflammation. In vitro, IL-4is necessary for differentiation of the naive CD-positive T-cells withinthe Th2 subpopulation secreting IL-4, IL-5, IL-6, IL-10 and IL-13.Although IL-4 induces IgE synthesis and enables the immediate type ofhypersensitivity reaction, there is certain evidence suggesting in vitroand in vivo anti-inflammatory effects of IL-4. IL-4 is critical inswitching B lymphocytes to produce IgE, for expression of VCAM-1 onendothelial cells, and for inducing the differentiation of Th2 cells andIL-5, which is essential for the differentiation of eosinophils.

The critical role of IL-5 in eosinophilia has been confirmed by the useof an anti-IL-5 antibody in asthmatic patients, which almost depletescirculating eosinophils and prevents eosinophil recruitment into theairway after allergen. IL-5 is a cytokine that is not encountered athigh levels in healthy individuals. The control of IL-5 proteinproduction takes place at the level of transcription. IL-10 is a potentanti-inflammatory cytokine that inhibits the synthesis of manyinflammatory proteins, including cytokines (TNF-α, granulocytemacrophage colony stimulating factor, IL-5, chemokines) and inflammatoryenzymes (inducible nitric oxide synthase) that are over-expressed inasthma. In addition, IL-10 inhibits antigen presentation andsensitisation. IL-13 signals through the IL-4 receptor α-chain, but mayalso activate different intracellular pathways.

Thus, IL-4, IL-5 and IL-10 are of critical importance in thedifferentiation of Th2 cells and are therefore ‘upstream’ cytokines thatare an attractive therapeutic target in the treatment of atopicdiseases.

In addition to Th2 cytokines, IgE-dependent activation of mast cells hasbeen suggested to play a role in allergic airway inflammation. WhereasIgE cross-linking by antigens did not induce eosinophil recruitment intothe airways or airway hyperreactivity, IgE cross-linking induced T cellrecruitment into the airways. In addition, when antigen-specific Th2cells were transferred to IgE transgenic mice, IgE cross-linkingsignificantly enhanced antigen-induced eosinophil recruitment into theairways. These findings suggest that IgE-dependent mast cell activationplays an important role in allergic airway inflammation by recruitingTh2 cells into the site of allergic inflammation.

Eosinophils are believed to be the final effector cells in thepathogenesis of allergic disease and bronchial asthma. These cells alsohave the capacity to synthesize and release a wide array of cytokines.Eosinophils can also secrete TGF-α and TGF-β and as such may account forthe eosinophil-derived stimulatory capacity for fibroblastproliferation, which leads to changes in the lung architecture and thusmay contribute to the irreversibility of bronchial asthma. Likewise,human eosinophils synthesize and secrete IL-6, which facilitates IL-4dependent IgE production (Coyle and Tsuyuki, 1995).

The IL-4 cytokine released from Th2 and Th2-like cells is likely to becentral to the pathophysiology of asthma and allergy in that itcontributes to aberrant IgE production, eosinophilia and, perhaps,mucosal susceptibility to viral infections. Accordingly, it wassuggested in Coyle and Tsuyuki (1995) that inhibitors of Th2 cytokineproduction will prove to be of therapeutic value. It was furthersuggested that inhibition of IL-4 may offer advantages in steroidresistant asthma by preventing/reversing impaired steroid receptorfunction and in viral mediated exacerbations of asthma, where IL-4 maybe of central importance in switching cytotoxic CD8+ T cells to a Th2like phenotype.

Viral infections are a major cause of worldwide morbidity and mortality.Acute and chronic viral infections cause direct pathology, but they canalso influence other concurrent responses (e.g. exacerbations of allergyof allergic diseases or autoimmunity) or in fact shape the immune systemin such a way that subsequent immune responses develop differently.Important examples are virally conferred protection or enhancement ofallergy subsequent to infection, or the development of immunodeficiencyin chronic infection.

For example, Respiratory-Syncytial-Virus (RSV) is a major respiratorypathogen that infects nearly all children by the age of 2 or 3; however,natural infection results in poor immunity and consequently people arenot protected against subsequent infection. Severe prior infection withRSV has been linked with an increased susceptibility to the developmentof asthma although the molecular mechanisms remain to be fullyelucidated. In addition, akin to Influenza virus infection, followingRSV infection there is an increased susceptibility to bacterialinfections and consequently impaired anti-bacterial responses. There arecurrently no vaccines available for RSV and prophylactic treatment withmonoclonal antibodies are the primary source of protection for infantsand the elderly.

It remains unclear how RSV manages to subvert protective immunity, andthe mechanisms by which infection may predispose people to asthmaremains highly debated. However, a tragic vaccine trial failure providedsome key insight into the pathogenic mechanisms: young childrenvaccinated with formalin inactivated RSV developed a profound Th2-basedimmune response upon subsequent natural infection by RSV, which in somecases was fatal.

It is known that pathogens such as viruses activate CD8+ T cells. Thesecells typically produce a Th1 like cytokine panel (INF-γ, IL-2) after invitro stimulation. CD8+ T cells are further known to mediate lysis ofviral infected cells and inhibition of viral replication through theproduction of IFN-γ.

However, it has recently been shown that viral antigen-specificactivation of CD8+ T cells in the presence of IL-4 may lead to a switchof CD8+ T cells towards a Th2 like phenotype that produces IL-5 andreduced amounts of IFN-γ. This phenotype switch may contribute to anexacerbation of asthma severity due to IL-5 production. Further, thereduced secretion of IFN-γ may impair the normal host response, leadingto delayed viral clearance from the lung. (Coyle and Tsuyuki (1995)).

Further viral infections leading to a worldwide morbidity and mortalityare caused by influenza viruses and require seasonal vaccination.

Even though vaccines against viral infections can be very effective,there is a clear need for improvements in terms of vaccine design andincreased adjuvant efficiency to promote vaccine action. In particular,the possibility of utilizing an adjuvant which required less vaccine toelicit protection against infection would be high valuable especiallyduring viral pandemics.

Accordingly, there is a desperate need for improved strategies fortreating viral infections such as RSV and Influenza, and/or forpreventing or ameliorating autoimmune diseases, allergicdisorders/diseases.

This need could be satisfied within the scope of the present inventionby providing compositions and methods for the modulation of a Th2 orTh2-like immune response towards a Th1 immune response, which leads toprevention or attenuation of viral infections and/or virus-inducedexacerbations of allergy or autoimmunity and of allergic disorders ingeneral.

In particular, it was surprisingly found within the scope of the presentinvention that short chain fatty acids as disclosed and claimed hereincan be used in human therapy for use in the treatment, prevention orattenuation of viral infections and/or virus-induced exacerbations ofallergy or autoimmunity and the treatment, prevention or attenuation ofallergic disorders in general upon transrnucosal, particularlyintranasal, particularly sublingual administration of the short chainfatty acids.

The present invention thus provides a compound of formula (I)

-   -   wherein    -   X represents —O—, —S—, or —NH—, preferably —O—;    -   R represents hydrogen, alkyl, aryl, arylalkyl, polyalkylene        glycol;    -   R₁ represents hydrogen, alkyl, hydroxyalkyl, arylalkylcarboxylic        acid;    -   R₂ represents hydrogen, alkyl, —O—R₃; and    -   R₃ represents hydrogen, aryl, arylalkyl, hydroxyalkyl-carboxyl;        or pharmaceutically acceptable salts thereof, for modulation of        a Th2 or Th2-like immune response towards a Th1 immune response        upon transmucosal administration, particularly upon intranasal,        particularly upon sublingual administration, to a subject.

In one embodiment, the present invention relates to a compound offormula (I)

-   -   wherein    -   X represents —O—, —S—, or —NH—, preferably —O—;    -   R represents hydrogen, alkyl, aryl, arylalkyl, polyalkylene        glycol;    -   R₁ represents hydrogen, alkyl, hydroxyalkyl, arylalkylcarboxylic        acid;    -   R₂ represents hydrogen, alkyl, —O—R₃; and    -   R₃ represents hydrogen, aryl, arylalkyl, hydroxyalkyl-carboxyl;        or pharmaceutically acceptable salts thereof for use in        transmucosal administration to a subject for the prevention,        attenuation or treatment of a disease or disorder associated        with a compromised Th1 immune response and/or an unwanted Th2 or        Th2-like immune response.

This may be achieved by modulation of a Th2 or Th2-like immune responsetowards a Th1 immune response

In one embodiment, the present invention relates to a compound offormula (I)

-   -   wherein    -   X represents —O—, —S—, or —NH—, preferably —O—;    -   R represents hydrogen, alkyl, aryl, arylalkyl, polyalkylene        glycol;    -   R₁ represents hydrogen, alkyl, hydroxyalkyl, arylalkylcarboxylic        acid;    -   R₂ represents hydrogen, alkyl, —O—R₃; and    -   R₃ represents hydrogen, aryl, arylalkyl, hydroxyalkyl-carboxyl;        or pharmaceutically acceptable salts thereof, for use in the        treatment, prevention or attenuation of viral infections and/or        virus-induced exacerbations of allergy or autoimmunity and/or        allergic diseases and disorders upon transmucosal        administration, particularly upon intranasal, particularly upon        sublingual administration, to a subject.

The compound of formula (I) may also be used as an adjuvant forinducing, promoting or enhancing an immune response in a subject treatedwith an immunogen, for example, an immunogen comprised in a vaccine,particularly a viral vaccine.

In one embodiment, the compound of formula (I) is a compound, wherein

-   -   X represents —O—, —S—, or —NH—, preferably —O—;    -   R represents hydrogen, alkyl, aryl, arylalkyl, polyalkylene        glycol;    -   R₁ represents hydrogen, alkyl, hydroxyalkylcarboxylic acid;    -   R₂ represents hydrogen, alkyl, —O—R₃; and    -   R₃ represents hydrogen, aryl, arylalkyl, hydroxyalkyl-carboxyl;    -   or pharmaceutically acceptable salts thereof.

In a specific embodiment the compound of formula (I) is a compoundaccording to the invention and as described herein in the variousembodiments, wherein

-   -   X represents —O—, —S—, or —NH—, preferably —O—;    -   R represents hydrogen, C₁-C₆ alkyl, unsubstituted or substituted        phenyl with one or more, same or different, substituents        selected from the group consisting of nitro, halogen, amino,        hydroxyl, cyano, C₁-C₄ alkyloxy or trifluoro;    -   R₁ represents hydrogencarboxylic acid, C₁-C₆ alkyl,        hydroxy-C₁-C₆ alkyl wherein the alkyl group may be unsubstituted        or substituted with one or more, same or different, substituents        selected from the group consisting of hydroxyl, amino,        carboxylic acid, halogen, cyano, or nitro;    -   R₂ represents hydrogen, C₁-C₆ alkyl, —O—R₃; and    -   R₃ represents hydrogen, unsubstituted or substituted phenyl with        one or more, same or different, substituents selected from the        group consisting of nitro, halogen, amino, hydroxyl, cyano,        C₁-C₄ alkyloxy or trifluoro, phenyl-C₁-C₆ alkyl wherein the        phenyl group may be unsubstituted or substituted with one or        more, same or different, substituents selected from the group        consisting of nitro, halogen, amino, hydroxyl, cyano, C₁-C₄        alkyloxy or trifluoro, hydroxy-C₁-C₆ alkyl-carboxyl;        or pharmaceutically acceptable salts thereof.

In another specific embodiment, the compound of formula (I) is acompound according to the invention and as described herein in thevarious embodiments, wherein

-   -   X is —O—,    -   R is hydrogen;    -   R₁ represents hydrogencarboxylic acid, C₁-C₄ alkyl,        hydroxy-C₁-C₄ alkyl wherein the alkyl group may be unsubstituted        or substituted with one or more, same or different, substituents        selected from the group consisting of hydroxyl, amino, or        carboxylic acid, preferably hydroxyl and/or carboxylic acid; and    -   R₂ is hydrogen or C₁-C₄ alkyl;    -   or pharmaceutically acceptable salts thereof.

In another specific embodiment, the compound of formula (I) is acompound according to the invention and as described herein in thevarious embodiments, wherein

-   -   X is —O—,    -   R is hydrogen;    -   R₁ represents hydrogencarboxylic acid, C₁-C₄ alkyl,        hydroxy-C₁-C₄ alkyl wherein the alkyl group may be unsubstituted        or substituted with one or more, same or different, substituents        selected from the group consisting of hydroxyl, amino or        carboxylic acid, preferably hydroxyl and/or carboxylic acid; and    -   R₂ is —OR₃; and    -   R₃ represents hydrogen, unsubstituted or substituted phenyl with        one or more, same or different, substituents selected from the        group consisting of nitro, halogen, amino, hydroxyl, cyano or        methoxy, phenyl-C₁-C₄ alkyl wherein the phenyl group may be        unsubstituted or substituted with one or more, same or different        substituents selected from the group consisting of nitro,        halogen, amino, hydroxyl, cyano or methoxy, hydroxy-C₁-C₃        alkyl-carboxyl;    -   or pharmaceutically acceptable salts thereof.

In another specific embodiment, the compound of formula (I) is acompound according to the invention and as described herein in thevarious embodiments, wherein

-   -   X is —O—,    -   R is hydrogen;    -   R₁ represents hydrogencarboxylic acid, C₁-C₃ alkyl,        hydroxy-C₁-C₃ alkyl wherein the alkyl group may be unsubstituted        or substituted with one or more, same or different, substituents        selected from the group consisting of hydroxyl and/or carboxylic        acid; and    -   R₂ is hydrogen or C₁-C₄ alkyl;    -   or pharmaceutically acceptable salts thereof.

In another specific embodiment, the compound of formula (I) is acompound according to the invention and as described herein in thevarious embodiments, wherein

-   -   X is —O—,    -   R is hydrogen;    -   R₁ represents hydrogen, carboxylic acid, C₁-C₃ alkyl,        hydroxy-C₁-C₃ alkyl wherein the alkyl group may be unsubstituted        or substituted with one or more, same or different, substituents        selected from the group consisting of hydroxyl or carboxylic        acid;    -   R₂ is —OR₃; and    -   R₃ represents hydrogen, unsubstituted or substituted phenyl with        one or more, same or different, substituents selected from the        group consisting of nitro, halogen, amino, hydroxyl, cyano or        methoxy, phenyl-C₁-C₄ alkyl wherein the phenyl group may be        unsubstituted or substituted with one or more, same or        different, substituents selected from the group consisting of        nitro, halogen, amino, hydroxyl, cyano, or methoxy,        hydroxy-C₁-C₃ alkyl-carboxyl;    -   or pharmaceutically acceptable salts thereof.

In particular, the compound of formula (I) is a compound according tothe invention and as described herein in the various embodiments,wherein

-   -   X is —O—,    -   R is hydrogen;    -   R₁ is selected from the group consisting of hydrogen, methyl,        ethyl, n-propyl, isopropyl, hydroxymethyl, dihydroxymethyl,        hydroxyethyldicarboxylic acid, carboxylic acidmethylcarboxylic        acid, hydroxymethylcarboxylic, ethylcarboxylic acid; and    -   R₂ is selected from the group consisting of hydrogen, hydroxyl        or methyl;    -   or pharmaceutically acceptable salts thereof, or wherein    -   X is —O—,    -   R is hydrogen;    -   R₁ is selected from the group consisting of hydrogen, methyl,        ethyl, n-propyl, isopropyl;    -   R₂ is —OR₃; and    -   R₃ is selected from the group consisting of        1-hydroxyethylcarbonyl, benzyl, nitrophenyl;    -   or pharmaceutically acceptable salts thereof.

In yet another specific embodiment, the compound of formula (I) is acompound according to the invention and as described herein in thevarious embodiments, wherein

-   -   X is —O—,    -   R represents C₁-C₄ alkyl, unsubstituted or substituted phenyl        with one or more, same or different, substituents selected from        the group consisting of nitro, halogen, amino, hydroxyl, cyano        or methoxy, phenyl-C₁-C₄ alkyl wherein the phenyl group may be        unsubstituted or substituted with one or more, same or        different, substituents selected from the group consisting of        halogen, nitro, amino, hydroxyl, cyano or methoxy, polyalkylene        glycol;    -   R₁ is carboxylic acid, C₁-C₄ alkyl or hydroxy-C₁-C₄ alkyl,        wherein the alkyl group may be unsubstituted or substituted with        one or more, same or different, substituents selected from the        group consisting of hydroxyl, amino or carboxylic acid; and    -   R₂ is hydrogen;    -   or pharmaceutically acceptable salts thereof.

In yet another specific embodiment, the compound of formula (I) is acompound according to the invention and as described herein in thevarious embodiments, wherein

-   -   X is —O—,    -   R represents C₁-C₄ alkyl, unsubstituted or substituted phenyl        with one or more, same or different, substituents selected from        the group consisting of nitro, halogen, amino, hydroxyl, cyano        or methoxy, phenyl-C₁-C₄ alkyl wherein the phenyl group may be        unsubstituted or substituted with one or more, same or        different, substituents selected from the group consisting of        halogen, nitro, amino, hydroxyl, cyano or methoxy, polyalkylene        glycol;    -   R₁ is carboxylic acid, C₁-C₃ alkyl or hydroxy-C₁-C₃ alkyl        wherein the alkyl group may be unsubstituted or substituted with        one or more, same or different, substituents selected from the        group consisting of hydroxyl and/or carboxylic acid; and    -   R₂ is hydrogen;    -   or pharmaceutically acceptable salts thereof.

In particular, the present invention thus provides a compound of formula(I)

wherein

-   -   X is —O—,    -   R is selected from the group consisting of methyl, ethyl,        propyl, benzyl, nitrobenzyl, polyethylene glycol;    -   R₁ selected from the group consisting of ethyl, hydroxyethyl,        methyl, hydroxymethyl; and    -   R₂ is hydrogen;    -   or pharmaceutically acceptable salts thereof for modulation of a        Th2 or Th2-like immune response towards a Th1 immune response        upon transmucosal administration, particularly upon intranasal,        particularly upon sublingual administration, to a subject.

The present invention further provides a compound of formula (I)

wherein

-   -   X is —O—,    -   R is selected from the group consisting of methyl, ethyl,        propyl, benzyl, nitrobenzyl, polyethylene glycol;    -   R₁ selected from the group consisting of ethyl, hydroxyethyl,        methyl, hydroxymethyl; and    -   R₂ is hydrogen;    -   or pharmaceutically acceptable salts thereof for use in the        treatment, prevention or attenuation of viral infections and/or        virus-induced exacerbations of allergy or autoimmunity upon        transmucosal administration, particularly upon intranasal,        particularly upon sublingual administration, to a subject.

In particular, the compound of formula (I) may also be used as anadjuvant for inducing, promoting or enhancing an immune response in asubject treated with an immunogen, for example, an immunogen comprisedin a vaccine, particularly a viral vaccine.

In a specific embodiment, the compound of formula (I) is a compoundaccording to the invention and as described herein in the variousembodiments selected from the group consisting of propionic acid, aceticacid, butyric acid, isobutyric acid, 2-hydroxyproirinic acid, dilacticacid, 2-benzyloxypropionic acid, 2-(p-nitrophenyl)-oxy-propionic acid,3-hydroxypropionic acid, 2,3-dihydroxypropionic acid, methyl3-hydroxypropionate, ethyl 3-hydroxypropionate, propyl3-hydroxypropionate, benzyl 3-hydroxypropionate, para-nitrophenyl3-hydroxypropionate, p-nitrobenzyl 3-hydroxypropionate, polyethyleneglycol 3-hydroxypropionate, methyl propionate, ethyl propionate, propylpropionate, benzyl propionate, p-nitrophenyl propionate, p-nitrobenzylpropionate, 2-(4-Isobutylphenyl) propionic acid, lactic acid, citricacid, malic acid, malonic acid, succinic acid, and tartaric acid; orpharmaceutically acceptable salts thereof.

In still another embodiment of the invention, the compound of formula(I) of the invention as described herein in the various embodiments isselected from the group consisting of isobutyric acid,3-hydroxypropionic acid, 2,3-dihydroxypropionic acid, lactic acid, orcitric acid, or pharmaceutically acceptable salts thereof.

In particular, the compound of formula (I) is propionic acid or apharmaceutically acceptable salt thereof.

The compounds of this invention may contain one or more asymmetriccenters and thus occur as racemates and racemic mixtures, singleenantiomers, individual diastereomers and diastereomeric mixtures. Allsuch isomeric forms of these compounds are expressly included in thepresent invention. The compounds of this invention may also containlinkages (e.g., carbon-carbon bonds) wherein bond rotation is restrictedabout that particular linkage, e.g. restriction resulting from thepresence of a ring or double bond. Accordingly, all cis-trans and E/Zisomers are expressly included in the present invention. The compoundsof this invention may also be represented in multiple tautomeric forms,in such instances, the invention expressly includes all tautomeric formsof the compounds described herein, even though only a single tautomericform may be represented (e.g., alkylation of a ring system may result inalkylation at multiple sites, the invention expressly includes all suchreaction products). All such isomeric forms of such compounds areexpressly included in the present invention. All crystal forms of thecompounds described herein are expressly included in the presentinvention.

The compounds of formula (I) of the invention as described herein in thevarious embodiments, but particularly propionic acid, or apharmaceutically acceptable salt thereof, or a composition comprisingthe SCFA compound of formula (I) according to the invention and asdescribed herein, but particularly propionic acid, or a pharmaceuticallyacceptable salt thereof, particularly in a therapeutically effectiveamount, optionally, together with a pharmaceutically acceptable carrierand/or a balanced salt solution as disclosed herein, is used fortransmucosal administration, particularly for sublingual administration,particularly for intranasal administration to a subject for thetreatment, prevention or attenuation of viral infections and/orvirus-induced exacerbations of allergy or autoimmunity and/or allergicdiseases and disorders.

The compounds of formula (I) of the invention as described herein in thevarious embodiments, but particularly propionic acid, or apharmaceutically acceptable salt thereof, or a composition comprisingthe SCFA compound of formula (I) according to the invention and asdescribed herein, but particularly propionic acid, or a pharmaceuticallyacceptable salt thereof, particularly in a therapeutically effectiveamount, optionally, together with a pharmaceutically acceptable carrierand/or a balanced salt solution as disclosed herein, may also be usedupon transmucosal administration, particularly upon sublingual,particularly upon intranasal administration, as an adjuvant forinducing, promoting or enhancing an immune response in a subject treatedwith an immunogen, for example, an immunogen comprised in a vaccine,particularly a viral vaccine.

In one embodiment, transmucosal administration, particularly sublingual,particularly intranasal administration, of a single or repetitive doseof said SCFA compound of formula (I) or a pharmaceutically acceptablesalt thereof, or a composition comprising the SCFA compound of formula(I) according to the invention and as described herein, or apharmaceutically acceptable salt thereof, optionally, together with apharmaceutically acceptable carrier, and/or a balanced salt solution asdisclosed herein, said SCFA compound or composition leads to a reductionof the virus titer in a treated subject, which is up to 5-fold,particularly up to 10-fold, particularly up to 25-fold, particularly upto 50-fold, particularly up to 100-fold, particularly up to 200-fold,particularly up to 500-fold, particularly up to 1000-fold, particularlyup to 2500-fold, particularly up to 5000-fold, particularly up to10000-fold more effective as compared to systemic administration, suchas for instance oral or intraperitoneal administration.

In certain embodiments, the present invention relates to a SCFA compoundof formula (I) according to the invention and as described herein or toa pharmaceutically acceptable salt thereof, or to a compositioncomprising the SCFA compound of formula (I) according to the inventionand as described herein, or a pharmaceutically acceptable salt thereof,particularly in a therapeutically effective amount, optionally, togetherwith a pharmaceutically acceptable carrier, and/or a balanced saltsolution as disclosed herein, for use in a method for inducingantigen-specific T cells in a subject, particularly of antigen-specificCD4+ T cells or CD8+ T cells or both, wherein said SCFA compound offormula (I) or a composition comprising the SCFA compound of formula (I)according to the invention and as described herein is administered to asubject in need thereof transmucosally, particularly intranasally,particularly sublingually.

The SCFA compound of formula (I) according to the invention and asdescribed herein is, in a specific embodiment, propionic acid or apharmaceutically acceptable salt thereof.

In one aspect of the invention, the CD8+ T cells are memory CD8+ Tcells.

In another aspect of the invention, said antigen-specific T cells areinduced in the airways, particularly in the lung of the subject.

In one embodiment, the SCFA compound of formula (I) or a compositioncomprising the SCFA compound of formula (I) according to the inventionand as described herein in the various embodiments, optionally togetherwith a balanced salt solution as disclosed herein, is used fortransmucosal administration, particularly for sublingual, particularlyfor intranasal administration to a subject for prevention, alleviationor treatment of a viral infection, particularly a viral infection in theairways of a subject.

In a specific embodiment, said SCFA compound of formula (I) according tothe invention and as described herein is propionic acid or apharmaceutically acceptable salt thereof.

In one embodiment, the SCFA compound of formula (I) or a compositioncomprising the SCFA compound of formula (I) according to the inventionand as described herein in the various embodiments, particularly apropionic acid or a pharmaceutically acceptable salt thereof, or acomposition comprising propionic acid or a pharmaceutically acceptablesalt thereof, optionally together with a balanced salt solution asdisclosed herein, is used for transmucosal administration, particularlyfor sublingual, particularly for intranasal administration to a subjectfor prevention, alleviation or treatment of a viral infection,particularly a viral infection in the airways of a subject

Accordingly, in one embodiment, the present invention relates to a SCFAcompound of formula (I) according to the invention and as describedherein in the various embodiments or to a pharmaceutically acceptablesalt thereof, or to a composition comprising the SCFA compound offormula (I) according to the invention and as described herein, or apharmaceutically acceptable salt thereof, particularly in atherapeutically effective amount, optionally, together with apharmaceutically acceptable carrier and/or a balanced salt solution asdisclosed herein, for use in transmucosal administration, particularlyin sublingual, particularly in intranasal administration to a subjectfor prevention, alleviation or treatment of a viral infection,particularly a viral infection in the airways of a subject, such asasthma, chronic obstructive pulmonary disease and autoimmunity orprevention of a disease or condition, particularly an allergic diseaseor disorder, or in amelioration of the condition of a subject sufferingfrom such a disease or disorder, including, but without being limitedto, an allergic disease or disorder selected from the group consistingof asthma, rhinitis, dermatitis, drug reactions, eosinophilic diseasesor disorders, esophageal and gastrointestinal allergy, or a combinationthereof.

In another embodiment of the invention, the SCFA compound of formula (I)according to the present invention and as described herein in thevarious embodiments or a composition comprising said compound isadministered alone, or, optionally, in combination with another compoundin a concentration of between 0.01 mg/kg and 1000 mg/kg body-weight,particularly between 0.1 mg/kg and 500 mg/kg body weight, particularlybetween 0.1 mg/kg and 100 mg/kg body-weight, particularly between 0.1mg/kg and 10 mg/kg body-weight, particularly between 0.5 mg/kg and 5mg/kg body-weight, particularly between 1 mg/kg and 5 mg/kg body-weightparticularly in a concentration of 1 mg/kg body-weight.

In a specific embodiment of the invention, said optional other compoundadministered together with the SCFA compound of formula (I) according tothe present invention is a balanced salt solution as disclosed herein,particularly, said balanced salt solution is optimized for theconditions in the nasal cavities, particularly, said balanced saltsolution is Locke-Ringer solution.

In another embodiment, the SCFA compound of formula (I) according topresent invention or a composition as disclosed herein comprising saidSCFA compound of formula (I) and optionally a balanced salt solution asdisclosed herein can be administered to a subject before, on the day of,or one or more days after the viral infection, to effectively reduce theviral titer in the treated subject. In a specific embodiment, saidcompound or composition of the invention can be administered to asubject one day after the infection. Surprisingly, such a post-infectiontreatment was found to be as effective as a treatment before or at theday of infection. The compound or composition according to the presentinvention and as described herein may be administered in a single doseor multiple doses throughout a 24-hour time period.

In a specific embodiment, said SCFA compound of formula (I) according tothe invention and as described herein is propionic acid or apharmaceutically acceptable salt thereof.

In a specific embodiment of the invention, said viral infection is,without being limited thereto, selected from the group consisting ofInfluenza virus, respiratory syncytial virus, metapneumonia virus (MPV),human immunodeficiency virus, vaccinia virus, variola virus, denguevirus, coxsackie virus, hepatitis A virus, poliovirus, rhinovirus,Herpes simplex, type 1, Herpes simplex, type 2, Varicella-zoster virus,Epstein-barr virus, Human cytomegalovirus, Human herpesvirus, HepatitisB virus, Hepatitis C virus, yellow fever virus, dengue virus, West Nilevirus, Measles virus, Mumps virus, Parainfluenza virus, Humanmetapneumovirus, Human papillomavirus, Rabies virus, Rubella virus,Human bocavirus, and Parvovirus 619 infection.

In another specific embodiment of the invention, said viral infection isan Influenza virus infection.

In particular, the SCFA compound of formula (I) or a compositioncomprising the SCFA compound of formula (I) according to the inventionand as described herein in the various embodiments, particularly apropionic acid or a pharmaceutically acceptable salt thereof, or acomposition comprising propionic acid, or a pharmaceutically acceptablesalt thereof, optionally together with a balanced salt solution asdisclosed herein, can also be used for transmucosal administration,particularly for sublingual, particularly for intranasal administrationto a subject for the treatment, prevention or amelioration of virallyconferred protection or enhancement of allergy subsequent to infection,or the virally-induced development of immunodeficiency in chronicinfection.

Other embodiments of the invention relate to a method for inducingantigen-specific T cells in a subject, particularly of antigen-specificCD4+ T cells or CD8+ T cells or both, particularly in the airways ofsaid subject, comprising transmucosally, particularly intranasally,particularly sublingually administering to said subject in need thereofa SCFA compound of formula (I) according to the invention and asdescribed herein in the various embodiments or a pharmaceuticallyacceptable salt thereof, or a composition comprising the SCFA compoundof formula (I) according to the invention and as described herein in thevarious embodiments, or a pharmaceutically acceptable salt thereof,particularly a propionic acid or a composition comprising propionicacid, or a pharmaceutically acceptable salt thereof, optionally togetherwith a balanced salt solution as disclosed herein, which leads to areduction of the amount of T helper 2 (Th2) cell-derived cytokines in asubject treated with said compound or composition, particularly in theairways of said subject. Transmucosal, particularly sublingual,particularly intranasal administration of the compound or compositionaccording to the invention may thus be used for the treatment orprevention of a disease or disorder mediated by T helper 2 (Th2)cell-derived cytokines, or for amelioration of the condition of asubject suffering from such a disease or disorder.

Other embodiments of the invention relate to a method for treatment,prevention, or attenuation of viral infections and/or virus-inducedexacerbations of allergic diseases or disorders such as asthma, chronicobstructive pulmonary disease and allergy or autoimmunity comprisingtransmucosally, particularly sublingually, particularly intranasallyadministering to a subject in need of such a treatment a therapeuticallyeffective amount of a SCFA compound of formula (I) or a compositioncomprising the compound of formula (I), or a pharmaceutically acceptablesalt thereof, particularly in a therapeutically effective amount,optionally, together with a pharmaceutically acceptable carrier. Inparticular, said composition may further comprise a balanced saltsolution as disclosed herein.

In a specific embodiment, said SCFA compound of formula (I) according tothe invention and as described herein is propionic acid or apharmaceutically acceptable salt thereof.

In one embodiment of the invention a method of inducing, promoting orenhancing an immune response to an immunogen in a subject is provided,for example, an immunogen comprised in a vaccine, particularly a viralvaccine comprising transmucosally administering to a subject in needthereof comprising a SCFA compound of formula (I) or a composition asdescribed herein, or a pharmaceutically acceptable salt thereof,particularly in a therapeutically effective amount, optionally, togetherwith a pharmaceutically acceptable carrier and/or a balanced saltsolution disclosed herein, wherein the transmucosal administration iseffected by intranasal, buccal, oral, transmucosal, intratracheal,intraurinary tract, intravaginal, sublingual, intrabronchial,intrapulmonary and/or transdermal administration.

In a specific embodiment of the invention a method of inducing,promoting or enhancing an immune response to an immunogen in a subjectis provided, wherein transmucosal administration of said compound orcomposition, optionally together with a pharmaceutically acceptablecarrier and/or a balanced salt solution as disclosed herein, is effectedintranasally or by inhalation. In a specific embodiment of the inventiona method of inducing, promoting or enhancing an immune response to animmunogen in a subject is provided, wherein transmucosal administrationof said compound or composition is effected by sublingualadministration.

In a specific embodiment of the invention, said viral infection is,without being limited thereto, selected from the group consisting ofInfluenza virus, respiratory syncytial virus, metapneumonia virus (MPV),human immunodeficiency virus, vaccinia virus, variola virus, denguevirus, coxsackie virus, hepatitis A virus, poliovirus, rhinovirus,Herpes simplex, type 1, Herpes simplex, type 2, Varicella-zoster virus,Epstein-barr virus, Human cytomegalovirus, Human herpesvirus, HepatitisB virus, Hepatitis C virus, yellow fever virus, dengue virus, West Nilevirus, Measles virus, Mumps virus, Parainfluenza virus, Humanmetapneumovirus, Human papillomavirus, Rabies virus, Rubella virus,Human bocavirus, and Parvovirus B19 infection.

The above compound or composition can also be used in a method forpreparing a medicament.

In still another embodiment, the invention relates to a SCFA compound offormula (I) according to the invention and as described herein in thevarious embodiments or to a pharmaceutically acceptable salt thereof, orto a composition comprising the SCFA compound of formula (I) accordingto the invention and as described herein in the various embodiments, ora pharmaceutically acceptable salt thereof, particularly in atherapeutically effective amount, optionally, together with apharmaceutically acceptable carrier, and/or a balanced salt solution,for use as an adjuvant in inducing, promoting or enhancing an immuneresponse in a subject treated with an immunogen, for example, animmunogen comprised in a vaccine, particularly a viral vaccine upontransmucosal administration, particularly upon intranasaladministration, particularly upon sublingual administration.

In one embodiment, the invention relates to a method of inducing,promoting or enhancing an immune response against an immunogen in asubject, comprising: (a) transmucosally, particularly sublingually,particularly intranasally administering an immunogen to a subject inneed thereof in an immunogenically effective amount; and (b)transmucosally, particularly intranasally, particularly sublinguallyadministering a SCFA compound of formula (I) according to the inventionand as described herein in the various embodiments or a pharmaceuticallyacceptable salt thereof, or a composition comprising the SCFA compoundof formula (I) according to the invention and as described herein in thevarious embodiments and optionally a balanced salt solution as disclosedherein.

In one embodiment, the invention relates to the use of a SCFA compoundof formula (I) according to the invention and as described herein in thevarious embodiments or of a pharmaceutically acceptable salt thereof, ora composition comprising the SCFA compound of formula (I) according tothe invention and as described herein in the various embodiments, or apharmaceutically acceptable salt thereof, as an adjuvant for inducing,promoting or enhancing an immune response against an immunogen, whereinsaid SCFA compound of formula (I) is administered to a subject in needthereof by transmucosal administration, particularly by sublingualadministration, particularly by intranasal administration. Inparticular, said immune response is primarily triggered or induced by aphysiologically balanced salt solution as disclosed herein.

The above compound or composition can also be used for preparing anadjuvant formulation or a medicament.

In certain embodiments of the invention, said viral vaccines areselected from the group consisting of vaccines towards Influenza virus,respiratory syncytial virus, metapneumonia virus (MPV), humanimmunodeficiency virus, vaccinia virus, variola virus, dengue virus,coxsackie virus, hepatitis A virus, poliovirus, rhinovirus, Herpessimplex, type 1, Herpes simplex, type 2, Varicella-zoster virus,Epstein-barr virus, Human cytomegalovirus, Human herpesvirus, HepatitisB virus, Hepatitis C virus, yellow fever virus, dengue virus, West Nilevirus, Measles virus, Mumps virus, Parainfluenza virus, Humanmetapneumovirus, Human papillomavirus, Rabies virus, Rubella virus,Human bocavirus, and Parvovirus B19 infections.

Further contemplated are vaccines selected from the group consisting ofa diphtheria vaccine, a pertussis vaccine, a tetanus vaccine, a poliovaccine, a hepatitis A vaccine, a hepatitis B vaccine, a rabies vaccine,a measles vaccine, a rubella vaccine, ain influenza vaccine, a mumpsvaccine, a varicella vaccine, a rota vaccine, a smallpox vaccine, ayellow fever vaccine, a mite-mediated encephalitis vaccine, an Hibvaccine, a typhoid vaccine, a cholera vaccine, a BCG vaccine, apneumococcus vaccine and a vaccine against meningitis caused byNeeisseria meningitidis.

Myeloid precursor cells, but particularly dendritic cells (DCs) arecrucial cell types required for inducing inflammatory responses, such asasthma. These cells capture antigens/allergens in the lung and transportthem to the draining lymphoid tissue where they activate T cells. TheseT cells then migrate back to the lung where they are reactivated bylung-resident dendritic cells, and elicit their effector functioncausing many of the symptoms of asthma (plus list of diseases). Myeloidprecursor cells, but particularly dendritic cells thus represent animportant rate-limiting step in the development of Th2 and Th17 driveninflammation and modifying their function is a powerful means ofregulating inflammation.

It has now been surprisingly found within the scope of the presentinvention that transmucosal administration, particularly sublingual,particularly intranasal administration of short chain fatty acids(SCFA), particularly of propionic acid or a pharmaceutically acceptablesalt thereof, can lead to a modulation of the number and/or theactivation state of myeloid precursor cells, but particularly ofdendritic cells (DCs) in an individual, particularly in the airways ofan individual, which has major implications on the use and theeffectiveness of said compounds in the prevention or amelioration ofviral infections, autoimmune diseases, and/or allergicdisorders/diseases. It has further been surprisingly found within thescope of the present invention that transmucosal administration,particularly sublingual, particularly intranasal administration, ofshort chain fatty acids (SCFA), particularly of propionic acid or apharmaceutically acceptable salt thereof, is capable of reducing therelease of cytokines from Th2 cells in model animals, but particularlythe release of IL-4, IL8 and/or IL-17A. These compounds were furthershown to reduce systemic IgE levels in model animals while leaving otherimportant antibody isotypes, including IgG2a, IgG2c and IgA, unaffected.Further, differential cell counts revealed that treatment of modelanimals with short chain fatty acids also lead to a reduction ofeosinophils.

Accordingly, short chain fatty acids of formula (I) according to thepresent invention as described herein in the various embodiments,particularly propionic acid or a pharmaceutically acceptable saltthereof, can be used for transmucosal administration, particularlysublingual, particularly intranasal administration in human therapy atan early stage for the treatment or, prevention of allergic diseases, orfor amelioration of the condition of a subject suffering from such adisease or disorder, particularly of a disease or disorder mediated by Thelper 2 (Th2) cell-derived cytokines, including, without being limitedto, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, and IL-17A, but particularlyof IL-4 and/or IL-8 and/or IL-17A and/or IgE mediated diseases ordisorders including, but without being limited to, allergic disordersincluding autoimmune diseases selected from asthma, rhinitis,dermatitis, drug reactions, esophageal and gastrointestinal allergy.

Short chain fatty acids of formula (I) according to the presentinvention as described herein in the various embodiments, particularlypropionic acid or a pharmaceutically acceptable salt thereof, canfurther be used for transmucosal administration, particularly forsublingual administration, particularly for intranasal administration,in human therapy for the treatment of eosinophilic diseases or disorderscomprising nodules, eosinophilia, eosinophilic rheumatism, dermatitisand swelling (NERDS).

In another embodiment, the present invention relates to a SCFA compoundof formula (I) according to the invention and as described herein in thevarious embodiments or to a pharmaceutically acceptable salt thereof, orto a composition comprising the SCFA compound of formula (I) accordingto the invention and as described herein in the various embodiments, ora pharmaceutically acceptable salt thereof, particularly in atherapeutically effective amount, optionally, together with apharmaceutically acceptable carrier and/or a balanced salt solution asdisclosed herein, for use in transdermal administration, particularlyfor use in sublingual administration, particularly for use in intranasaladministration in a subject, for modulating the number and/or theactivation state of myeloid precursor cells, but particularly dendriticcells (DCs) in the affected tissue or organ of the treated subject

In a specific embodiment, said SCFA compound of formula (I) according tothe invention and as described herein is propionic acid or apharmaceutically acceptable salt thereof.

In another embodiment, the present invention relates to a SCFA compoundof formula (I) according to the invention and as described herein in thevarious embodiments or to a pharmaceutically acceptable salt thereof, orto a composition comprising the SCFA compound of formula (I) accordingto the invention and as described herein in the various embodiments, ora pharmaceutically acceptable salt thereof, particularly in atherapeutically effective amount, optionally, together with apharmaceutically acceptable carrier, and/or a balanced salt solution asdisclosed herein for use in a method for the prevention of developmentof a Th2 induced inflammatory condition in a tissue or organ of asubject, the method comprising transmucosally, particularlysublingually, particularly intranasally administering an effectiveamount of a compound of formula (I) to the subject, which compoundmodulates the number and/or the activation state of myeloid precursorcells, but particularly dendritic cells (DCs) in the affected tissue ororgan of the treated subject, particularly prior to the activation of aT cell response.

In a specific embodiment, said SCFA compound of formula (I) according tothe invention and as described herein is propionic acid or apharmaceutically acceptable salt thereof.

In another embodiment, the present invention relates to a compound offormula (I) according to the invention and as described herein in thevarious embodiments or to a pharmaceutically acceptable salt thereof, orto a composition comprising the SCFA compound of formula (I) accordingto the invention and as described herein in the various embodiments, ora pharmaceutically acceptable salt thereof, particularly in atherapeutically effective amount, optionally, together with apharmaceutically acceptable carrier and/or a balanced salt solution asdisclosed herein, for use in human or animal therapy comprisingadministering said compound or composition transmucosally, particularlysublingually, particularly intranasally to a subject for reducing therelease of cytokines from Th2 cells and/or of systemic IgE levels, whileleaving other antibody isotypes, including IgG2a and IgG2c, unaffectedand/or reducing eosinophil infiltration, resulting in treatment orprevention of an associated disease or disorder, or amelioration of thecondition of a subject suffering from such a disease or disorder, suchas an allergic disease or disorder.

In yet another embodiment, the present invention relates to a compoundof formula (I) according to the invention and as described herein in thevarious embodiments or to a pharmaceutically acceptable salt thereof, orto a composition comprising the SCFA compound of formula (I) accordingto the invention and as described herein in the various embodiments, ora pharmaceutically acceptable salt thereof, particularly in atherapeutically effective amount, optionally, together with apharmaceutically acceptable carrier and/or a balanced salt solution asdisclosed herein, for use in human or animal therapy comprisingadministering said compound or composition transmucosally, particularlyintranasally, particularly sublingually to a subject for reducing therelease of cytokines from Th2 cells and/or of systemic IgE levels, whileleaving other antibody isotypes, including IgG2a and IgG2c, unaffectedand/or reducing eosinophil infiltration, resulting in treatment orprevention of an associated disease or disorder, or amelioration of thecondition of a subject suffering from such a disease or disorder, suchas an allergic disease or disorder.

In another certain embodiment, the present invention relates to a SOFAcompound of formula (I) according to the invention and as describedherein in the various embodiments or to a pharmaceutically acceptablesalt thereof, or to a composition comprising the SCFA compound offormula (I) according to the invention and as described herein in thevarious embodiments, or a pharmaceutically acceptable salt thereof,particularly in a therapeutically effective amount, optionally, togetherwith a pharmaceutically acceptable carrier, for use in modulating thebarrier function and integrity of epithelial cells comprisingadministering said compound or composition transmucosally, particularlyintranasally, particularly sublingually to a subject in need thereof. Inparticular, said composition optionally comprises a physiologicallybalanced salt solution as disclosed herein, which has positive effectson the barrier function and integrity of epithelial cells. Such positiveeffects are for instance an increased or stabilized mucociliaryfunction, such as an increased or stabilized cilia movement and/orincreased or stabilized epithelial barrier integrity.

In a specific embodiment, said SOFA compound of formula (I) according tothe invention and as described herein is propionic acid or apharmaceutically acceptable salt thereof.

In another certain embodiment, the present invention relates to a SCFAcompound of formula (I) according to the invention and as describedherein in the various embodiments or to a pharmaceutically acceptablesalt thereof, or to a composition comprising the SCFA compound offormula (I) according to the invention and as described herein in thevarious embodiments, or a pharmaceutically acceptable salt thereof,particularly in a therapeutically effective amount, optionally, togetherwith a pharmaceutically acceptable carrier and/or a balanced saltsolution as disclosed herein for use in modulating the activity ofmembers of the IL-1 family and the inflammasome comprising administeringsaid compound or composition transmucosally, particularly intranasally,particularly sublingually, to a subject in need thereof.

In a specific embodiment, said SCFA compound of formula (I) according tothe invention and as described herein is propionic acid or apharmaceutically acceptable salt thereof.

In another embodiment of the invention, the SCFA compound of formula (I)according to the invention and as described herein in the variousembodiments or a pharmaceutically acceptable salt thereof, or acomposition comprising the SCFA compound of formula (I) according to theinvention and as described herein in the various embodiments, optionallytogether with a balanced salt solution as disclosed herein, may be usedin a method of modulating the number and/or the activation state ofmyeloid precursor cells, but particularly dendritic cells (DCs) in anindividual, particularly in the airways of an individual comprisingadministering said compound or composition transmucosally, particularlyintranasally, particularly sublingually, to a subject in need thereof.Said compounds or compositions can thus be used for an early stagetreatment or prevention of allergic diseases, particularly of a diseaseor disorder mediated by T helper 2 (Th2) cell-derived cytokines,including, without being limited to, IL-4, IL-5, IL-6, IL-8, IL-10,IL-13, and IL-17A, but particularly of IL-4 and/or IL-8 and/or IL-17Aand/or IgE mediated diseases or disorders including, but without beinglimited to, allergic disorders including autoimmune diseases selectedfrom asthma, rhinitis, dermatitis, drug reactions, esophageal andgastrointestinal allergy.

In particular, the compound of formula (I) or a pharmaceuticallyacceptable salt thereof for use in a method for the prevention ofdevelopment of a Th2 induced inflammatory condition in a tissue or organof a subject, the method comprising transmucosal administering aneffective amount of a compound of formula (I) to the subject, whereinsaid subject suffers from IgE-mediated disease or disorder and whereinthe IgG and/or IgA levels in the treated subject remain unaffected orare increased.

In a specific embodiment of the invention the compound of formula (I) ora pharmaceutically acceptable salt thereof is provided for use in amethod in reducing the IL-4 release from Th2 cells in a subjectsuffering from an IL-4 mediated disease or disorder.

Short chain fatty acids of formula (I) according to the invention and asdescribed herein in the various embodiments, particularly propionic acidor a pharmaceutically acceptable salt thereof, can further be used inhuman therapy for the treatment, particularly for the early stagetreatment of eosinophilic diseases or disorders comprising nodules,eosinophilia, eosinophilic rheumatism, dermatitis and swelling (NERDS).

In one embodiment, the present invention relates to a SCFA compound offormula (I) according to the invention and as described herein in thevarious embodiments or to a pharmaceutically acceptable salt thereof, orto a composition comprising the SCFA compound of formula (I) accordingto the invention and as described herein in the various embodiments, ora pharmaceutically acceptable salt thereof, particularly in atherapeutically effective amount, optionally, together with apharmaceutically acceptable carrier and/or a balanced salt solution, foruse in human or animal therapy comprising administering said compound orcomposition transmucosally, particularly intranasally, particularlysublingually, to a subject for reducing the circulating levels ofimmunogen-specific IgE in a subject treated with said compound andexposed to an immunogen, and thus for use in the treatment or preventionof an IgE mediated disease or disorder, or for amelioration of thecondition of a subject suffering from such a disease or disorder.

In a specific embodiment, said SCFA compound of formula (I) according tothe invention and as described herein is propionic acid or apharmaceutically acceptable salt thereof, optionally together with abalanced salt solution as disclosed herein.

In one embodiment, the present invention relates to a SCFA compound offormula (I) according to the invention and as described herein in thevarious embodiments or to a pharmaceutically acceptable salt thereof, orto a composition comprising the SCFA compound of formula (I) accordingto the invention and as described herein in the various embodiments, ora pharmaceutically acceptable salt thereof, particularly in atherapeutically effective amount, optionally, together with apharmaceutically acceptable carrier, and/or a balanced salt solution asdisclosed herein for use in human or animal therapy comprisingadministering said compound or composition transmucosally, particularlyintranasally, particularly sublingually, to a subject for reducing thenumber of eosinophils in a subject treated with said compound andexposed to an immunogen, particularly in the airways of said subject,and thus for use in the treatment or prevention of an eosinophilicdisease or disorder, or for amelioration of the condition of a subjectsuffering from such a disease or disorder.

In one embodiment, the disease or disorder is an allergic disease ordisorder mediated by T helper 2 (Th2) cell-derived cytokines, including,without however being limited to, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13or IL-17A, or certain combinations thereof, particularly an IL-4 and/orIL-8, and/or IL-17A mediated disease or disorder, and/or an IgE mediateddisease or disorder, particularly a disease or disorder selected fromthe group consisting of allergic asthma, hay fever, drug allergies,allergic bronchopulmonary aspergillosis (ABPA), esophageal and agastrointestinal allergy, pemphigus vulgaris, atopic dermatitis,onchocercal dermatitis, viral infections such as Respiratory SyncytialVirus infection or a combination thereof.

In one embodiment, the asthma is steroid resistant asthma, neutrophilicasthma or non-allergic asthma.

In one embodiment, the allergic disease or disorder is an eosinophilicdisease or disorder, particularly a disease or disorder selected fromthe group consisting of nodules, eosinophilia, eosinophilic rheumatism,dermatitis and swelling (NERDS).

In another embodiment, the allergic disease or disorder is anIgE-mediated disease or disorder, particularly a disease or disorderselected from the group consisting of urticaria, eczema conjunctivitis,rhinorrhea, rhinitis, particularly allergic rhinitis, gastroenteritis,or a combination thereof.

In still another embodiment, an IgE-mediated disease or disordercomprises myeloma, multiple myeloma, Hodgkin's disease, Hyper-IgEsyndrome, Wiskott-Aldrich syndrome, Chronic Obstructive PulmonaryDisease and exacerbations of Chronic Obstructive Pulmonary Disease or acombination thereof.

In certain embodiments, the invention relates to a method for modulatingthe number and/or the activation state of myeloid precursor cells, butparticularly dendritic cells (DCs) in the affected tissue or organ, saidmethod comprising administering transmucosally, particularlyintranasally, particularly sublingually, at an early stage to a subjectin need of such a treatment a therapeutically effective amount of a SCFAcompound of formula (I) or of a composition comprising the compound offormula (I), or a pharmaceutically acceptable salt thereof, particularlyin a therapeutically effective amount, optionally, together with apharmaceutically acceptable carrier and/or a balanced salt solution asdisclosed herein, particularly prior to the activation of a T cellresponse.

In particular, the invention relates to a method for the prevention ofdevelopment of a Th2 induced inflammatory condition in a tissue or organof a subject, the method comprising administering an effective amount ofa compound of formula (I) to the subject transmucosally, particularlyintranasally, particularly sublingually, which compound modulates thenumber and/or the activation state of myeloid precursor cells, butparticularly dendritic cells (DCs) in the affected tissue or organ. Inparticular, said method comprises administering transmucosally,particularly intranasally, particularly sublingually, at an early stageto a subject in need of such a treatment a therapeutically effectiveamount of a SCFA compound of formula (I) or of a composition comprisingthe compound of formula (I), or a pharmaceutically acceptable saltthereof, particularly in a therapeutically effective amount, optionally,together with a pharmaceutically acceptable carrier and/or a balancedsalt solution as disclosed herein, particularly prior to the activationof a T cell response.

Other embodiments of the invention relate to a method for the treatmentor prevention of a disease or disorder mediated by T helper 2 (Th2)cell-derived cytokines, including, without however being limited to,IL-4, IL-5, IL-6, IL-8, IL-10, IL-13 or IL-17A, or certain combinationsthereof, particularly an IL-4 and/or IL-8, and/or IL-17A mediateddisease or disorder, and/or an IgE mediated disease or disorder and/oran eosinophilic disease or disorder, or for amelioration of thecondition of a subject suffering from such a disease or disorder, saidmethod comprising administering transmucosally, particularlyintranasally, particularly sublingually, to a subject in need of such atreatment a therapeutically effective amount of a SCFA compound offormula (I) or of a composition comprising the compound of formula (I),or a pharmaceutically acceptable salt thereof, particularly in atherapeutically effective amount, optionally, together with apharmaceutically acceptable carrier and/or a balanced salt solution.

In one embodiment, the invention relates to a method for selectivelycontrolling, particularly for selectively reducing, allergen-specificIgE antibody levels in a subject suffering from IgE-mediated disease ordisorder comprising administering transmucosally, particularlyintranasally, particularly sublingually, to a subject in need of such atreatment a therapeutically effective amount of a SCFA compound offormula (I) or of a composition comprising the compound of formula (I),or a pharmaceutically acceptable salt thereof, in a therapeuticallyeffective amount, optionally, together with a pharmaceuticallyacceptable carrier and/or a balanced salt solution. In a specificembodiment, such a treatment does not affect or increases IgG levels,particularly IgG2a, IgG2c levels, and/or IgA levels, in the treatedsubject.

In one embodiment, the invention relates to a method for reducing therelease of IL-4, and/or IL-8, and/or IL-17A, from Th2 cells in a subjectsuffering from an IL-4, and/or IL-8, and/or IL-17A mediated disease ordisorder comprising administering transmucosally, particularlyintranasally, particularly sublingually, to a subject in need of such atreatment a therapeutically effective amount of a SCFA compound offormula (I) or of a composition comprising the compound of formula (I),or a pharmaceutically acceptable salt thereof, particularly in atherapeutically effective amount, optionally, together with apharmaceutically acceptable carrier and/or a balanced salt solution. Ina specific embodiment, such a treatment also reduces theallergen-specific IgE antibody levels in a subject, but does not affector increases IgG levels, particularly IgG2a, IgG2c levels, and/or IgAlevels, in the treated subject.

In another embodiment, the invention relates to a method for use in thetreatment or prevention of an allergic disease or disorder, or foramelioration of the condition of a subject suffering from an allergicdisease or disorder, including, but without being limited to, anallergic disease or disorder selected from the group consisting ofasthma, rhinitis, dermatitis, drug reactions, eosinophilic diseases ordisorders, esophageal and gastrointestinal allergy, or a combinationthereof comprising administering transmucosally, particularlyintranasally, particularly sublingually, to a subject in need of such atreatment a therapeutically effective amount of a SCFA compound offormula (I) or of a composition comprising the compound of formula (I),or a pharmaceutically acceptable salt thereof, particularly in atherapeutically effective amount, optionally, together with apharmaceutically acceptable carrier and/or a balanced salt solution.

In a specific embodiment, said SCFA compound of formula (I) according tothe invention and as described herein is propionic acid or apharmaceutically acceptable salt thereof.

In one embodiment, the allergic disease or disorder is an IL-4- and/orIL-8- and/or IL-17A-mediated disease or disorder and/or an IgE mediateddisease or disorder, particularly a disease or disorder selected fromthe group consisting of allergic asthma, hay fever, drug allergies,allergic bronchopulmonary aspergillosis (ABPA), esophageal and agastrointestinal allergy, pemphigus vulgaris, atopic dermatitis,onchocercal dermatitis, or a combination thereof.

In one embodiment, the allergic disease or disorder is an eosinophilicdisease or disorder, particularly a disease or disorder selected fromthe group consisting of nodules, eosinophilia, eosinophilic rheumatism,dermatitis and swelling (NERDS).

In another embodiment, the allergic disease or disorder is anIgE-mediated disease or disorder, particularly a disease or disorderselected from the group consisting of urticaria, eczema conjunctivitis,rhinorrhea, rhinitis, particularly allergic rhinitis, gastroenteritis,or a combination thereof.

In still another embodiment, an IgE-mediated disease or disordercomprises myeloma, multiple myeloma, Hodgkin's disease, Hyper-IgEsyndrome, Wiskott-Aldrich syndrome, or a combination thereof.

In certain embodiments, the present invention provides a method for themanufacture of the compositions according to the invention and asdescribed herein in the various embodiments comprising one or more SOFAcompound of formula (I) according to the invention and as describedherein in the various embodiments as active ingredients which processcomprises mixing one or more SCFA compounds of formula (I) with an inertcarrier or excipient that is acceptable to the target organism that isin need of the treatment, optionally together with a balanced saltsolution.

In several embodiments of the inventions, the balanced salt solution asused therein is Locke-Ringer solution.

In various embodiments of the invention, administration of SOFA asdisclosed herein or a composition comprising said SOFA as disclosedherein, particularly propionic acid or a pharmaceutically acceptablesalt thereof, or a composition comprising propionic acid or apharmaceutically acceptable salt thereof, together with a balanced saltsolution as disclosed herein, particularly Locke-Ringer solution leadsto an elevated Th1 immune response and/or reduced Th2 immune responsecompared to the single administration of said SOFA or compositioncomprising said SCFA or balanced salt solution.

In various embodiments of the inventions, administration of SCFA asdisclosed herein or a composition comprising said SCFA as disclosedherein, particularly propionic acid or a pharmaceutically acceptablesalt thereof, or a composition comprising propionic acid or apharmaceutically acceptable salt thereof, together with a balanced saltsolution as disclosed herein, particularly Locke-Ringer solution leadsto a more efficient treatment of asthma, chronic obstructive pulmonarydisease and autoimmunity compared to the single administration of saidSCFA or composition comprising said SCFA or balanced salt solution. Inparticular, wherein said diseases or disorders are caused by viralinfections.

DEFINITIONS

The technical terms and expressions used within the scope of thisapplication are generally to be given the meaning commonly applied tothem in the pertinent art if not otherwise indicated herein below.

As used in this specification and the appended claims, the singularforms “a”, “an”, and “the” include plural referents unless the contextclearly dictates otherwise. Thus, for example, reference to “a compound”includes one or more compounds.

“Alkyl” as such means a straight-chained or branched saturated aliphatichydrocarbon having from 1 to 10 carbon atoms, wherein the alkyl groupmay be unsubstituted or substituted with one or more, same or different,substituents selected from the group consisting of hydroxyl, amino,carboxylic acid, halogen, cyano, or nitro. Preferred are C₁-C₆ alkyl,such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, n-pentyl (amyl), 2-pentyl (sec-pentyl), 3-pentyl,2-methylbutyl, 3-methylbutyl (=iso-pentyl or iso-amyl),3-methylbut-2-yl, 2-methylbut-2-yl, 2,2-dimethylpropyl (=neopentyl),n-hexyl, iso-hexyl, sec.-hexyl, tert.-hexyl and the like. Most preferredare C₁-C₄ alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl.

“Hydroxyalkyl” stands for one of the above-defined alkyl groups whereinat least one hydrogen atom is replaced by a hydroxyl group and whereinthe hydroxyalkyl group may be unsubstituted or substituted with one ormore, same or different, substituents selected from the group consistingof hydroxyl, amino, carboxylic acid, halogen, cyano, or nitro. Typicalrepresentatives are —CH₂OH, —CH₂CH₂OH, —CH(OH)—CH₃, —CH(OH)CH₂CH₃,CH₂CH(CH₂CH₂OH)CH₂CH etc.

“Aryl” means a monovalent, monocyclic, bicyclic or tricyclic, aromaticcarbocyclic hydrocarbon radical, preferably a 6-14 member aromatic ringsystem. Preferred aryl groups include, but are not limited to phenyl,naphthyl, phenanthrenyl, and anthracenyl, wherein the aryl group may beunsubstituted or substituted with one or more, same or differentsubstituents selected from the group consisting of halogen; alkyl;alkyloxy; cyano, trifluoro, nitro, amino, hydroxyl.

“Alkoxy” means —O-alkyl, wherein alkyl has the meaning given above.“Halogen” means fluorine, chlorine, bromine, or iodine, preferablyfluorine, chlorine or iodine.

“Polyalkylene glycol” means a moiety that comprises at least twoaklylene glycol units such as —O-alkyl-O-alkyl-O- moiety wherein alkylhave the meaning given above. The polyalkylene glycol moiety may besolely comprised of polyalkylene glycol, or may be part of a largerstructure, such as polyoxyalkylated glycerol and other polyoxyalkylatedpolyols such as polyoxyethylated sorbitol or polyoxyethylated glucose.The number of alkylene units may vary and is greater than 1. Preferred,polyalkylene glycol are polyethylene glycol (PEG) or polypropyleneglycol (PPG). Most preferred polyalkylene glycol are PEG wherein thenumber of ethylene units may vary from 8 to 150.000 or more,particularly from 10 to 80.000, more particularly from 20 to 10.000.

The term “compound of formula (I)” and “composition comprising thecompound of formula (I)” is meant to also refer to a pharmaceuticallyacceptable salt of the compound of formula (I).

The term “propionate” refers to the pharmaceutically acceptable salt ofpropionic acid such as, for example, the sodium salt of propionic acid.

The term “pharmaceutically acceptable salts” include salts of acidic orbasic groups present in compounds of the invention. Pharmaceuticallyacceptable acid addition salts include, but are not limited to,hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate,phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate,citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate,maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate,formate, benzoate, glutamate, methanesulfonate, ethanesulfonate,benzensulfonate, p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain compounds ofthe invention can form pharmaceutically acceptable salts with variousamino acids. Suitable base salts include, but are not limited to,aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, anddiethanolamine salts.

The terms “treatment”, “treating” and the like are used herein togenerally mean obtaining a desired pharmacological and/or physiologicaleffect. The effect may be prophylactic in terms of completely orpartially preventing a disease or symptom thereof and/or may betherapeutic in terms of partially or completely curing a disease and/oradverse effect attributed to the disease. The term “treatment” as usedherein covers any treatment of a disease in a subject and includes: (a)preventing a disease related to an undesired immune response fromoccurring in a subject which may be predisposed to the disease; (b)inhibiting the disease, i.e. arresting its development; or (c) relievingthe disease, i.e. causing regression of the disease.

A “patient” or “subject” for the purposes of the present invention isused interchangeably and meant to include both humans and other animals,particularly mammals, and other organisms. Thus, the methods areapplicable to both human therapy and veterinary applications. In thepreferred embodiment the patient or subject is a mammal, and in the mostpreferred embodiment the patient or subject is a human.

The term “attenuation” as used herein refers to reduction of a viralinfection in a subject or in a tissue of a subject, particularly in lungtissue of a subject, i.e. reduction or clearance of the amount of virusor viral load. The particular degree or level of the reduction orclearance is at least 15%, 25%, 35%, 50%, 65%, 75%, 80%, 85%, 90%, 95%,98% or more.

The term “adjuvant” as used herein refers to a substance that increasesor promotes the ability of an immunogen (i.e., antigen) to stimulate animmune response against the immunogen in the subject subjected to theimmunogen. In particular embodiments, the adjuvant increases the immuneresponse against the immunogen by at least 2, 3, 4, 5, 10, 15, 20, 30,40, 50, 60, 75, 100, 150, 500, 1000-fold or more. In other embodiments,the adjuvant reduces the amount of immunogen required to achieve aparticular level of immune response (cellular and/or humoral and/ormucosal), e.g., a reduction of at least 15%, 25%, 35%, 50%, 65%, 75%,80%, 85%, 90%, 95%, 98% or more. An adjuvant can further be a substancethat prolongs the time over which an immune response, optionallyprotective immune response, is sustained (e.g., by at least a 2-fold,3-fold, 5-fold, 10-fold, 20-fold longer time period or more).

The terms “myeloid precursors”, “myeloid lineage” or “myeloid cells”refer all to multipotent stem cells as one of two lineages ofhematopoietic cells, which are able to develop into monocytes,macrophages, dendritic cells, neutrophils, eosinophils, basophils,megacaryocytes, platelets or erythrocytes.

A “modulating compound” refers to a compound as described herein in thevarious embodiments, which may either up-regulate (e.g., activate orstimulate), down-regulate (e.g., inhibit or suppress) or otherwisechange a functional property or biological activity of a target moleculeor gene. A modulating compound may act to modulate a target molecule ora gene encoding said target molecule either directly or indirectly. Incertain embodiments, a modulating compound may be an activating compoundor an-inhibiting compound.

The “modulation of a Th2 or Th2-like immune response towards a Th1immune response” refers to a change from a “humoral immune response”executed mainly by antibodies, B cells, plasma cells and/or memory Bcells towards a “cellular immune response, executed mainly by CD8+ Tcells and phagocytes, e.g. macrophages. This modulation implements alsoa change in the cytokine composition which is characteristic for each ofthe two distinct T helper cell mechanisms. A Th2 or Th2-like immuneresponse is mediated by IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, and/orIL-17A, particularly IL-4 and/or IL-8 and/or IL-17A, whereas a Th1immune response is mediated by interferon-gamma (IFN-gamma), IL-2, andtumor necrosis factor-alpha (TNF-alpha). Further “modulation” meansparticularly prior to the activation of a T cell response.

The expressions “pharmaceutical composition” and “therapeuticalcomposition” are used herein interchangeably in the widest sense. Theyare meant to refer, for the purposes of the present invention, to atherapeutically effective amount of the active ingredient, i.e. the SCFAcompound of formula (I) or a pharmaceutically acceptable salt thereof,optionally, together with a pharmaceutically acceptable carrier and/or abalanced salt solution.

It embraces compositions that are suitable for the curative treatment,the control, the amelioration, an improvement of the condition or theprevention of a disease or disorder in a human being or a non-humananimal. Thus, it embraces pharmaceutical compositions for the use in thearea of human or veterinary medicine. Such a “therapeutic composition”is characterized in that it embraces at least one SCFA compound offormula (I) compound or a physiologically acceptable salt thereof, andoptionally a carrier and/or a balanced salt solution whereby the saltand the carrier and balanced salt solution are tolerated by the targetorganism that is treated therewith.

The terms “balanced salt solution” or “physiologically balanced saltsolution” as used hereinrefers to a salt solution with stable osmolalityand pH value between 6.5 and 7.6 and defined ion composition reflectingthe ratio of ions in the human body, particularly the nasal respiratorymucosa. An example for a suitable balanced salt solution according tothe present invention is Locke-Ringer solution (osmolality of about 328mosmol; pH of about 7.4). However, also other salt solution may besuitable, if the ion composition of these salt solutions reflectsessentially the ratio of ions in the human body and contains abiological inert buffer substance.

A “therapeutically effective amount” refers to that amount whichprovides a therapeutic effect for a given condition and administrationregimen. In particular, “therapeutically effective amount” means anamount that is effective to prevent, alleviate or ameliorate symptoms ofthe disease or prolong the survival of the subject being treated, whichmay be a human or non-human animal. Determination of a therapeuticallyeffective amount is within the skill of the person skilled in the art.

The therapeutically effective amount or dosage of a compound accordingto this invention can vary within wide limits and may be determined in amanner known in the relevant art. The dosage can vary within wide limitsand will, of course, have to be adjusted to the individual requirementsin each particular case.

The term “transmucosal” administration refers to various administrationroutes whereas the compound is absorbed by the mucosa of any part of thebody. Transmucosal administration comprises, but is not limited to, i.e.intranasal, buccal, oral transmucosal, intratracheal, intraurinarytract, intravaginal, sublingual, intrabronchial, intrapulmonary andtransdermal administration.

An “immunogenically effective amount” refers to that amount of animmunogen which provides an active immune response (cellular and/orhumoral) in a subject. In some embodiments of the invention, said immuneresponse is sufficient to provide a protective effect, which does notneed to be complete or permanent. Determination of an immunogenicallyeffective amount is within the skill of the person skilled in the art.

An “adjuvant effective amount” refers to that amount of an adjuvant thatenhances or stimulates the active immune response (cellular and/orhumoral or optionally an active mucosal immune response) provided by theimmunogen in a subject when subjected to the immunogen.

In the context of protective immune responses, the term “adjuvanteffective amount” refers to an amount of the adjuvant that is needed toaccelerate the induction of the immune response in the host and/or maybe sufficient to reduce the need for booster immunizations to achieveprotection.

In the context of prolongation of an immune response, the term “adjuvanteffective amount” refers to an amount that prolongs the time period overwhich an immune response, optionally protective immune response, issustained.

Determination of an adjuvant effective amount in the above addressedcontexts is within the skill of the person skilled in the art.

The SCFAs of formula (I) may be provided as such or in form of acomposition, particularly a pharmaceutical composition. Saidcompositions may comprise additional medicinal agents, balanced saltsolutions, pharmaceutical agents, carriers, buffers, adjuvants,dispersing agents, diluents, and the like depending on the intended useand application. In particular, said composition comprises a balancedsalt solution, such as Locke-Ringer solution. Saline solutions exhibitspecific influences on the functionality of the mucociliary system,especially on the frequency of ciliary movement, depending on thecomposition, the osmolality and the pH-value of the solution. Balancedsalt solutions containing potassium and calcium ions and a buffer (likeLocke-Ringer solution) exhibited an elevation or stabilization of thefrequency of ciliary movement of the bronchial epithelium as pureisotonic sodium chloride.

Administration of the suitable (pharmaceutical) compositions containingthe active ingredient according to the invention and as disclosedherein, may be effected by routes of administration, e.g., byintranasal, buccal, oral, transmucosal, intratracheal, intraurinarytract, intravaginal, sublingual, intrabronchial, intrapulmonary andtransdermal administration.

The composition as described herein is a liquid, liquid spray,microspheres, semisolid, gel, or powder for transmucosal administration,e.g. intranasal, buccal, oral transmucosal, intratracheal, intraurinarytract, intravaginal, sublingual, intrabronchial, intrapulmonary and/ortransdermal administration. Further, the composition is a solid dosageform for buccal, oral transmucosal and/or sublingual administration.Intranasal, buccal, oral intratracheal, intraurinary tract,intravaginal, transmucosal and sublingual administrations lead to thedisintegration of the composition as described herein in an oral cavityat body temperature and optionally may adhere to the body tissue of theoral cavity. Additionally, the composition as disclosed herein furthermay include one or more excipient, diluent, binder, lubricant, glidant,disintegrant, desensitizing agent, emulsifier, mucosal adhesive,solubilizer, suspension agent, viscosity modifier, ionic tonicity agent,buffer, carrier, balanced salt solution, surfactant, flavor, or mixturethereof.

In a specific aspect the composition is formulated as a tablet, pill,bioadhesive patch, sponge, film, lozenge, hard candy, wafer, sphere,lollipop, disc-shaped structure, or spray.

Transmucosal administration is generally rapid because of the richvascular supply to the mucosa and the lack of a stratum corneum in theepidermis. Such drug transport typically provides a rapid rise in bloodconcentrations, and similarly avoids the enterohepatic circulation andimmediate destruction by gastric acid or partial first- pass effects ofgut wall and hepatic metabolism. Drugs typically need to have prolongedexposure to a mucosal surface for significant drug absorption to occur.

The transmucosal routes can also be more effective than the oral routein that these routes can provide for relatively faster absorption andonset of therapeutic action. Further, the transmucosal routes can bepreferred for use in treating patients who have difficulty in swallowingtablets, capsules, or other oral solids, or those who havedisease-compromised intestinal absorption. Accordingly, there are manyadvantages to transmucosal administration of SCFAs.

In either of the intranasal or buccal routes, drug absorption can bedelayed or prolonged, or uptake may be almost as rapid as if anintravenous bolus were administered. Because of the high permeability ofthe rich blood supply, the sublingual route can provide a rapid onset ofaction.

The intranasal compositions of the invention, but particularly anintranasal composition comprising propionic acid or a pharmaceuticallyacceptable salt thereof, can be administered by any appropriate methodaccording to their form. A composition including microspheres or apowder can be administered using a nasal insufflator device. Examples ofthese devices are well known to those of skill in the art, and includecommercial powder systems such as Fisons Lomudal System. An insufflatorproduces a finely divided cloud of the dry powder or microspheres. Theinsufflator is preferably provided with a mechanism to ensureadministration of a substantially fixed amount of the composition. Thepowder or microspheres can be used directly with an insufflator, whichis provided with a bottle or container for the powder or microspheres.Alternatively, the powder or microspheres can be filled into a capsulesuch as a gelatin capsule, or other single dose device adapted for nasaladministration. The insufflator preferably has a mechanism to break openthe capsule or other device. Further, the composition can provide aninitial rapid release of the active ingredient followed by a sustainedrelease of the active ingredient, for example, by providing more thanone type of microsphere or powder. Further, alternative methods suitablefor administering a composition to the nasal cavity will be well knownby the person of ordinary skill in the art. Any suitable method may beused. For a more detailed description of suitable methods reference ismade to EP2112923, EP1635783, EP1648406, EP2112923 (the entire contentsof which are incorporated herein by reference).

The compounds of the present invention and the pharmaceuticalcompositions containing said compounds may be further administeredintranasally, i.e. by inhalation and thus may be formulated in a formsuitable for intranasal administration, i.e. as an aerosol or a liquidpreparation.

One exemplary formulation for intranasal delivery of the compoundaccording to the invention and as described herein, but particularly ofpropionic acid or a pharmaceutically acceptable salt thereof, is aliquid preparation, preferably an aqueous based preparation, suitablefor application as drops into the nasal cavity.

Alternatively, a liquid preparation may be placed into an appropriatedevice so that it may be aerosolized for inhalation through the nasalcavity. For example, the therapeutic agent may be placed into a plasticbottle atomizer. In one embodiment, the atomizer is advantageouslyconfigured to allow a substantial amount of the spray to be directed tothe upper one-third region or portion of the nasal cavity. For example,as delivery device the 3K®-System from the company Ursatec VerpackungGmbH (Germany) may be used. The 3K®-System is a patented,microbiologically safeguarded dosing system which is especially suitablefor administration of liquid pharmaceuticals via the nasal route. Withconventional multidose-systems, the outlet openings of the dosing unitsare not protected. Impurities and germs can contaminate the containerand the solution. Therefore, the contents of such containers must beadequately protected against microbiological deterioration by theaddition of suitable preservatives. However, preservatives are harmfuland have especially negative effects on the physiological mucociliarydefence system of the nasal mucosa.

Additionally, the liquid preparation may be aerosolized and applied viaan inhaler, such as a metered-dose inhaler. One example of a preferreddevice is that disclosed in U.S. Pat. No. 6,715,485, and which involvesa bi-directional delivery concept. In using the device, the end of thedevice having a sealing nozzle is inserted into one nostril and thepatient or subject blows into the mouthpiece. During exhalation, thesoft palate closes due to positive pressure thereby separating the nasaland oral cavities. The combination of closed soft palate and sealednozzle creates an airflow in which drug particles are released enteringone nostril, turning 180 degrees through the communication pathway andexiting through the other nostril, thus achieving bi-directional flow.

The compound according to the invention and as described herein, butparticularly propionic acid or a pharmaceutically acceptable saltthereof, may also be delivered in the form of a dry powder, as in knownin the art. An example of a suitable device is the dry powder nasaldelivery device marketed under the name DIRECTHALER™ nasal, and which isdisclosed in PCT publication No. 96/222802. This device also enablesclosing of the passage between the nasal and oral cavity during dosedelivery. Another device for delivery of a dry or liquid preparation isthe device sold under the trade designation OPTINOSE™.

Further examples of suitable delivery devices are provided inWO2002068029, EP2462972, the disclosure, of which is incorporated hereinby reference.

In the methods of the invention the animal can be a rodent, primate,human or other animal with a nasal cavity. Examples of suitablepharmaceutical carriers, excipients and/or diluents are well known inthe art and include, but are not limited to, a gum, a starch (e.g. cornstarch, pregeletanized starch), a sugar (e.g., lactose, mannitol,sucrose, dextrose), a cellulosic material (e.g. microcrystallinecellulose), an acrylate (e.g. polymethylacrylate), calcium carbonate,magnesium oxide, talc, or mixtures thereof.

Pharmaceutically acceptable carriers for liquid formulations are aqueousor non-aqueous solutions, suspensions, emulsions or oils. Examples ofnon-aqueous solvents are propylene glycol, polyethylene glycol, andinjectable organic esters such as ethyl oleate. Examples of oils arethose of animal, vegetable, or synthetic origin, for example, peanutoil, soybean oil, olive oil, sunflower oil, fish-liver oil, anothermarine oil, or a lipid from milk or eggs.

Aqueous carriers include water, alcoholic/aqueous solutions, emulsionsor suspensions, including saline and buffered media such as phosphatebuffered saline solutions, water, emulsions, such as oil/wateremulsions, various types of wetting agents, sterile solutions etc.Compositions comprising such carriers can be formulated by well knownconventional methods. Suitable carriers may comprise any material which,when combined with the biologically active compound of the invention,retains the biological activity.

Efforts have been made in the art to chemically modify the barrierproperties of skin to permit the penetration of certain agents, enhancethe effectiveness of the agent being delivered, enhance delivery times,reduce the dosages delivered, reduce the side effects from variousdelivery methods, reduce patient reactions, and so forth.

In this regard, penetration enhancers have been used to increase thepermeability of the dermal surface to drugs, and are often protonaccepting solvents such as dimethyl sulfoxide (DMSO) anddimethylacetamide. Other penetration enhancers that have been studiedand reported as effective include 2-pyrrolidine, N,N-diethyl-m-toluamide(Deet), 1-dodecal-azacycloheptane-2-one N,N-dimethylformamide,N-methyl-2-pyrrolidine, calcium thioglycolate, hexanol, fatty acids andesters, pyrrolidone derivatives, derivatives of 1,3-dioxanes and1,3-dioxolanes, 1-N-dodecyl-2-pyrrolidone-5-carboxylic acid,2-pentyl-2-oxo-pyrrolidineacetic acid,2-dodecyl-2-oxo-1-pyrrolidineacetic acid,1-azacycloheptan-2-one-2-dodecylacetic acid, and aminoalcoholderivatives, including derivatives of 1,3-dioxanes, among others.

Preparations for transmucosal administration may include sterile aqueousor non-aqueous solutions, suspensions, and emulsions. Examples ofnon-aqueous solvents are propylene glycol, polyethylene glycol,vegetable oils such as olive oil, and injectable organic esters such asethyl oleate. Aqueous carriers include water, alcoholic/aqueoussolutions, emulsions or suspensions, including saline and bufferedmedia. Transmucosal vehicles may include sodium chloride solution,Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, orfixed oils. Preservatives and other additives may also be presentincluding, for example, antimicrobials, anti-oxidants, chelating agents,and inert gases and the like. In addition, the pharmaceuticalcomposition of the present invention might comprise proteinaceouscarriers, like, e.g., serum albumin or immunoglobulin, preferably ofhuman origin.

The compounds of the present invention and as described herein in thevarious embodiments and the pharmaceutical compositions containing saidcompounds may be administered topically to body surfaces and thus beformulated in a form suitable for topical administration. Suitabletopical formulations include gels, ointments, creams, lotions, drops andthe like. For topical administration, the compound of formula (I) isprepared and applied as a solution, suspension, or emulsion in aphysiologically acceptable diluent with or without a pharmaceuticalcarrier.

The pharmaceutical compositions provided herein may also be administeredas controlled-release compositions, i.e. compositions in which theactive ingredient is released over a period of time afteradministration. Controlled- or sustained-release compositions includeformulation in lipophilic depots (e.g. fatty acids, waxes, oils). Inanother embodiment, the composition is an immediate-release composition,i.e. a composition in which all the active ingredient is releasedimmediately after administration.

Further examples for suitable formulations are provided in WO2006/085983, the entire contents of which are incorporated by referenceherein. For example, the SCFAs of the present invention may be providedas liposomal formulations. The technology for forming liposomalsuspensions is well known in the art. When the adjuvant is anaqueous-soluble salt, using conventional liposome technology, the samecan be incorporated into lipid vesicles. The lipid layer employed can beof any conventional composition and can either contain cholesterol orcan be cholesterol-free. The liposomes can be reduced in size, asthrough the use of standard sonication and homogenization techniques.Liposomal formulations containing the adjuvant can be lyophilized, aloneor with immunogen, to produce a lyophilizate which can be reconstitutedwith a pharmaceutically acceptable carrier, such as water, to regeneratea liposomal suspension. These pharmaceutical compositions can beadministered to the subject at a suitable dose. The dosage regimen willbe determined by the attending physician and clinical factors. As iswell known in the medical arts, dosages for any one patient depend uponmany factors, including the patient's size, body surface area, age, theparticular compound to be administered, sex, time and route ofadministration, general health, and other drugs being administeredconcurrently.

The SCFA compounds of formula (I) and as described herein in the variousembodiments may used in human and veterinary medicine for treatinghumans and animals, including avians, non-human primates, dogs, cats,pigs, goats, sheep, cattle, horses, mice, rats and rabbits.

Suitable dosages of the SCFAs according to the invention and asdescribed herein in the various embodiments will vary depending upon thecondition, administration route, age and species of the subject, and canbe readily determined by those skilled in the art. The total dailydosages of the compound of formula (I) employed in both veterinary andhuman medicine will suitably be in the range of between 0.01 mg/kg and1000 mg/kg body-weight, particularly between 0.1 mg/kg and 500 mg/kgbody weight, particularly between 0.1 mg/kg and 100 mg/kg body-weight,particularly between 0.1 mg/kg and 10 mg/kg body-weight, particularlybetween 0.5 mg/kg and 5 mg/kg body-weight, particularly between 1 mg/kgand 5 mg/kg body-weight particularly in a concentration of 1 mg/kgbody-weight and these may be administered as single or divided doses,and in addition, the upper limit can also be exceeded when this is foundto be indicated. Such dosage will be adjusted to the individualrequirements in each particular case including the specific compound(s)being administered, the route of administration, the condition beingtreated, as well as the patient being treated. However, the compoundscan also be administered as depot preparations (implants, slow-releaseformulations, etc.) weekly, monthly or at even longer intervals. In suchcases the dosage will be much higher than the daily one and has to beadapted to the administration form, the body weight and the concreteindication. The appropriate dosage can be determined by conductingconventional model tests, preferably animal models. An effective dose ofactive ingredient(s) depends at least on the nature of the conditionbeing treated, toxicity, whether the compound(s) is being usedprophylactic ally (lower doses) or against an active infection orcondition, the method of delivery, and the pharmaceutical formulation,and will be determined by the clinician using conventional doseescalation studies.

If used as an adjuvant, the SCFA compound of the invention and asdescribed herein in the various embodiments and/or the immunogen may begiven in form of a single or multiple (i.e., booster) dosage.

The immunogen and adjuvant can be co-administered concurrently (e.g.,within hours of each other) in the same or different composition and, inthe latter case, by the same or different route. Alternatively, theadjuvant can be administered prior to or after administration of theimmunogen (e.g., about 6, 12, 24, 36, 48, 72, 96 or 120 hours or morebefore or after administration of the immunogen).

Further, if used as an adjuvant, the SCFA compound of the invention andas described herein in the various embodiments may administered mixedwith immunogen, such as viral antigens, to enhance the immune responseelicited against these antigens or alternatively the compound may bechemically coupled to the immunogen directly or in the case of particles(e.g. nanoparticles or virus-like particles (VLP)) the compound could bebound to the surface or encapsulated within said particles.

Furthermore, it is envisaged that the pharmaceutical composition of theinvention might comprise further biologically active agents, dependingon the intended use of the pharmaceutical composition. These furtherbiologically active agents may be e.g. physiologically balanced saltsolutions, antibodies, antibody fragments, hormones, growth factors,enzymes, binding molecules, cytokines, chemokines, nucleic acidmolecules and drugs. In a preferred embodiment, the pharmaceuticalcomposition of the present invention is to be co-administered with otherknown immunosuppressive drug or treatments. Such immunosuppressive drugsmay be selected from the group consisting of glucocorticoids,cytostatics such as methotrexate, myophenolate or azathioprine,antibodies such as T cell receptor directed antibodies or IL-4 receptordirected antibodies and drugs acting on immunophilins such ascyclosporine, tacrolimus, sirolimus and the like.

The present invention further contemplates the use of a SCFA compound offormula (I) according to the invention and as described herein in thevarious embodiments or a pharmaceutically acceptable salt thereof, or ofa composition comprising the SCFA compound of formula (I) according tothe invention and as described herein in the various embodiments, or apharmaceutically acceptable salt thereof, in a therapeutically effectiveamount, optionally, together with a pharmaceutically acceptable carrier,and/or a balanced salt solution as disclosed herein, for use as anadjuvant in promoting or enhancing an immune response in a subject inneed thereof.

The immunogen can be any immunogen known in the art and can beadministered in any suitable form as described, for example, in WO2006/085983, the entire contents of which are incorporated by referenceherein.

For example, the immunogen can be in the form of a live, attenuatedlive, or killed (i.e., inactivated) organism (e.g., a bacterium orprotozoan) or virus, or an extract or toxoid thereof. In otherembodiments, the immunogen can be provided as an isolated component(e.g., a polypeptide or a peptide [e.g., from about 6 to 20 or 8 to 12amino acids in length]). Further, the immunogen can be administered perse or can be expressed from a nucleic acid that is administered to thehost and the immunogen expressed therefrom. The immunogen can comprise Bcell and/or T cell epitopes as are known in the art. The immunogen canfurther be soluble or particulate (e.g., microspheres).

In the alternative, the immunogen can be present in the organism. Forexample, in the case of a chronic or latent infection in the subject,the subject fails to mount a sufficient immune response against theantigen. The adjuvants of the invention can be administered to thesubject to induce an immune response against the antigen already presentin the subject as a result of the infection.

The immunogen can be an immunogen from an infectious agent, a cancerimmunogen, an allergic reaction immunogen (i.e., an allergen), atransplantation immunogen, an autoantigen, and the like as are known inthe art such as those described in WO 2006/085983.

The cancer that may be treated or immunized against (i.e., prophylactictreatment) by administration to a subject of the adjuvant of theinvention can be a cancer selected from the group consisting of B celllymphoma, T cell lymphoma, myeloma, leukemia, hematopoietic neoplasias,thymoma, lymphoma, sarcoma, lung cancer, liver cancer, non-Hodgkinslymphoma, Hodgkins lymphoma, uterine cancer, adenocarcinoma, breastcancer, pancreatic cancer, colon cancer, lung cancer, renal cancer,bladder cancer, liver cancer, prostate cancer, ovarian cancer, primaryor metastatic melanoma, squamous cell carcinoma, basal cell carcinoma,brain cancer, angiosarcoma, hemangiosarcoma, head and neck carcinoma,thyroid carcinoma, soft tissue sarcoma, bone sarcoma, testicular cancer,uterine cancer, cervical cancer, gastrointestinal cancer, and any othercancer now known or later identified (see, e.g., Rosenberg (1996) Ann.Rev. Med. 47:481-491, the entire contents of which are incorporated byreference herein).

Further immunogens contemplated within the scope of the presentinvention are infectious agent immunogens that can include any immunogensuitable for protecting a subject against an infectious disease,including but not limited to microbial, bacterial, protozoal, parasiticand viral diseases.

Examples of such infectious agent immunogens are disclosed in WO2006/085983 and can include, but are not limited to, immunogens fromHepadnaviridae including hepatitis A, B, C, D, E, F, G, etc.;Flaviviridae including human hepatitis C virus (HCV), yellow fever virusand dengue viruses; Retroviridae including human immunodeficiencyviruses (HIV), simian immunodeficiency virus (SIV), and human Tlymphotrophic viruses (HTLV1 and HTLV2); Herpesviridae including herpessimplex viruses (HSV-1 and HSV-2), Epstein Barr virus (EBV),cytomegalovirus, varicella-zoster virus (VZV), human herpes virus 6(HHV-6) human herpes virus 8 (HHV-8), and herpes B virus; Papovaviridaeincluding human papilloma viruses; Rhabdoviridae including rabies virus;Paramyxoviridae including respiratory syncytial virus; Reoviridaeincluding rotaviruses; Bunyaviridae including hantaviruses; Filoviridaeincluding Ebola virus; Adenoviridae; Parvoviridae including parvovirusB19; Arenaviridae including Lassa virus; Orthomyxoviridae includinginfluenza viruses; Poxviridae including Orf virus, molluscum contageosumvirus, smallpox virus and Monkey pox virus; Togaviridae includingVenezuelan equine encephalitis virus; Coronaviridae including coronaviruses such as the severe acute respiratory syndrome (SARS) virus; andPicornaviridae including polioviruses; rhinoviruses; orbiviruses;picodnaviruses; encephalomyocarditis virus (EMV); Parainfluenza viruses,adenoviruses, Coxsackieviruses, Echoviruses, Rubeola virus, Rubellavirus, human papillomaviruses, Canine distemper virus, Canine contagioushepatitis virus, Feline calicivirus, Feline rhinotracheitis virus. TGEvirus (swine), Foot and mouth disease virus, simian virus 5, humanparainfluenza virus type 2, human metapneuomovirus, enteroviruses, andany other pathogenic virus now known or later identified (see, e.g.,Fundamental Virology, Fields et al., Eds., 3<rd>ed., Lippincott-Raven,N.Y., 1996, the entire contents of which are incorporated by referenceherein for the teachings of pathogenic viruses).

Further, the immunogen may be an orthomyxovirus immunogen (e.g., aninfluenza virus immunogen, such as the influenza virus hemagglutinin(HA) surface protein, influenza neuraminidase protein, the influenzavirus nucleoprotein (NP) antigen or inactivated influenza virions, or anequine influenza virus immunogen), or a metapneumonia virus immunogen,or a lentivirus immunogen (e.g., an equine infectious anemia virusimmunogen, a SIV immunogen, or a HIV immunogen, such as, e.g., HIV orSIV gp120, gp160, gp41, or matthdcapsid protein, or the gag, pol or envgene products). The immunogen may also be an arenavirus immunogen (e.g.,Lassa fever virus immunogen, such as the Lassa fever virus nucleocapsidprotein gene and the Lassa fever envelope glycoprotein gene), aPicornavirus immunogen (e.g., a Foot and Mouth Disease virus immunogen),a poxvirus immunogen (e.g., a vaccinia immunogen, such as the vacciniaL1 or L8 genes), an Orbivirus immunogen (e.g., an African horse sicknessvirus immunogen), a flavivirus immunogen (e.g., a yellow fever virusimmunogen, a West Nile virus immunogen, or a Japanese encephalitis virusimmunogen), a filovirus immunogen (e.g., an Ebola virus immunogen, or aMarburg virus immunogen, such as NP and GP genes), a bunyavirusimmunogen (e.g., RVFV, CCHF, and SFS immunogens), a norovirus immunogen(e.g., a Norwalk virus immunogen), or a coronavirus immunogen (e.g., aninfectious human coronavirus immunogen, such as the human coronavirusenvelope glycoprotein gene, or a porcine transmissible gastroenteritisvirus immunogen, or an avian infectious bronchitis virus immunogen). Theimmunogen may further be a polio antigen, herpes antigen (e.g., CMV,EBV, HSV antigens) mumps antigen, measles antigen, rubella antigen,diptheria toxin or other diptheria antigen, pertussis antigen, hepatitis(e.g., hepatitis A or hepatitis B) antigen (e.g., HBsAg, HBcAg, HBeAg),or any other vaccine immunogen known in the art.

In particular, the immunogen may be from an influenza virus, respiratorysyncytial virus, metapneumonia virus (MPV), human immunodeficiencyvirus, vaccinia virus, variola virus, dengue virus, coxsackie virus,hepatitis A virus, poliovirus, rhinovirus, Herpes simplex, type 1,Herpes simplex, type 2, Varicella-zoster virus, Epstein-barr virus,Human cytomegalovirus, Human herpesvirus, Hepatitis B virus, Hepatitis Cvirus, yellow fever virus, dengue virus, West Nile virus, Measles virus,Mumps virus, Parainfluenza virus, Human metapneumovirus, Humanpapillomavirus, Rabies virus, Rubella virus, Human bocavirus, ParvovirusB19.

The immunogen can further be an immunogen from a pathogenicmicroorganism, including, without being limited to, Rickettsia,Chlamydia, Mycobacteria, Clostridia, Corynebacteria, Mycoplasma,Ureaplasma, Legionella, Shigella, Salmonella, pathogenic Escherichiacoli species, Bordatella, Neisseria, Treponema, Bacillus, Haemophilus,Moraxella, Vibrio, Staphylococcus spp., Streptococcus spp.,Campylobacter spp., Borrelia spp., Leptospira spp., Erlichia spp.,Klebsiella spp., Pseudomonas spp., Helicobacter spp., and any otherpathogenic microorganism now known or later identified (see, e.g.,Microbiology, Davis et al, Eds., 4thed., Lippincott, N.Y., 1990, theentire contents of which are incorporated herein by reference for theteachings of pathogenic microorganisms).

The immunogen can further be an immunogen from pathogenic protozoa orpathogenic yeast and fungi.

The immunogen can also be an immunogen from chronic or latent infectiveagents, which typically persist because they fail to elicit a strongimmune response in the subject. Illustrative latent or chronic infectiveagents include, but are not limited to, hepatitis B, hepatitis C,Epstein-Barr Virus, herpes viruses, human immunodeficiency virus, andhuman papilloma viruses.

Immunogens that are allergens are also contemplated by the presentinvention, which can include but are not limited to, environmentalallergens such as dust mite allergens; plant allergens such as pollen,including ragweed pollen; insect allergens such as bee and ant venom;and animal allergens such as cat dander, dog dander and animal salivaallergens.

Accordingly, the compounds of formula (I) according to the invention andas described herein in the various embodiments may be used for allergyimmunotherapy wherein the compound could be administered with togetherwith the allergens to improve the development of tolerance,desensitization or immune deviation towards the allergen.

Further examples of allergens contemplated within the scope of thepresent invention are disclosed in WO 2006/085983 including ragweedallergen or grass allergen. Ragweed, and in particular Short Ragweed(Ambrosia artemisiifolia), is clinically the most important source ofseasonal aeroallergens, as it is responsible for both the majority ofcases and the most severe cases of allergic rhinitis (Pollart, et al.(1989) J. Allergy Clin. Immunol. 83(5):875-82; Rosenberg, et al. (1983)J. Allergy Clin. Immunol. 71(3):302-10; Bruce, et al. (1977) J. AllergyClin. Immunol. 59(6): 449-59). Ragweed pollen also contributessignificantly to exacerbation of asthma and allergic conjunctivitis.

Other exemplary food, animal, tree, insect and mold allergens are foundat http://www.allergen.org/List.htm Marsh and Freidhoff. 1992. ALBE, anallergen database. (IUIS, Baltimore, Md. Edition 1.0).

The immunogen can further be an autoantigen (for example, to enhanceself-tolerance to an autoantigen in a subject, e.g., a subject in whomself-tolerance is impaired). Examples of autoantigens contemplatedwithin the scope of the present invention are disclosed in WO2006/085983 including, without being limited to, actin, myelin basicprotein, islet cell antigens, insulin, collagen and human collagenglycoprotein 39, muscle acetylcholine receptor and its separatepolypeptide chains and peptide epitopes, glutamic acid decarboxylase andmuscle-specific receptor tyrosine kinase, nicotinic acetylcholinereceptor, transglutaminase, oxoglutarate dehydrogenase complex,branched-chain alpha-keto acid dehydrogenase complex, apolioprotein H,nucleoprotein 62, RA33, Sp100 nuclear antigen and nucleoporin 210 kDa.

The adjuvant according to the present invention represented by acompound of formula (I) as described herein in the various embodimentscan be used for a variety of purposes and administered in various wayswell known to those skilled in the art.

An exemplary disclosure of purposes and methods for administering anadjuvant is provided in WO 2006/085983. In particular, the adjuvantaccording to the invention may be used generally in active or passiveimmunization for producing antibodies in vivo or in vitro, or in methodsof producing antibodies against an immunogen for any other purpose,e.g., for diagnostics or for use in histological techniques.

The adjuvant may further be used in human or veterinary therapy orprophylaxis. In particular, the adjuvant of the invention can beadministered to a subject as a general immune enhancer to increase bothinnate and adaptive immune function in the subject, for example, inimmunocompromised subjects such as subjects undergoing chemotherapy,radiation therapy, subjects with chronic infections (e.g., HCV and HBV)and/or subjects with HIV/AIDs. The invention can further be practiced toenhance the immune response to an attenuated live virus, a killedvaccine, or a DNA vaccine, all of which can have the disadvantage ofreduced immunogenicity. The adjuvant of the invention can further beused to treat a chronic or latent infection to induce or enhance theimmune response against the antigen(s) produced by the infection.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1: shows BALB/c mice which were administered with saline or sodiumpropionate (100 mg/kg) intranasally on days −3, −1, and 0. On day 0 allmice were infected with Influenza virus strain PR8. On day 5 postinfection, mice were sacrificed, lungs isolated and viral loaddetermined by PCR. Prophylactic treatment with sodium propionateadministered intranasally resulted in a markedly lower viral load in thelungs of mice, as compared to mice treated with saline alone. These datashow that sodium propionate exhibits efficacy in the protection againstinfluenza virus infection when administered directly into the airways.

FIG. 2: shows BALB/c mice which were treated with saline or sodiumpropionate (100 mg/kg) intranasally on day −1 and 0. On Day 0 mice wereinfected with 1×10⁶ PFU of Metapneumoia virus (MPV) A1 6621 intranasallyand on day 5 post infection, mice were sacrificed, lungs removed andviral load determined by quantitative PCR. These data show that sodiumpropionate exhibits efficacy in the protection against MPV infectionwhen administered directly into the airways.

FIGS. 3 A-D: show BALB/c mice which were treated with sodium propionate(100 mg/kg) or saline intranasally on day −5 and −3 (pretreatmentgroup), or day −5, −3, 0, 2 and 4 (pretreatment and priming group), orday −5, −3, 0, 2, 4, 7, 9, 11 (pretreatment, priming and challengegroup). On days 0, 2, 4, 7, 8 and 11 mice were exposed to 15 ug of housedust mite extract (Greer) intranasally. On day 14, all mice weresacrificed and bronchoalveolar lavage (BAL) was performed with sterilePBS. The total number of macrophages (FIG. 3B), eosinophils (FIG. 3A),lymphocytes (FIG. 3C) and neutrophils (FIG. 3D) was determined by totaland differential cell counts using standard morphological andcytochemical techniques. The data show that all treatment regimesresulted in statistically significant reductions in airway eosinophiliaindicative of a protective effect against the allergic response.

FIG. 4: shows BALB/c mice which were treated with saline or sodiumpropionate (100 mg/kg, 10 mg/kg, 1 mg/kg) intranasally on day 0. On day0 all mice were infected with Influenza virus strain PR8. On day 5 postinfection, mice were sacrificed, lungs isolated and viral loaddetermined by PCR. All doses of sodium propionate yielded in a markedlylower viral load in the lungs of mice, as compared to mice treated withsaline alone. These data show that a dose of 1 mg/kg sodium propionateadministered intranasally on day 0 exhibits efficacy in the protectionagainst influenza virus infection when administered directly into theairways.

FIG. 5: shows BALB/c mice which were treated with sodium propionate (100mg, 10 mg/kg, 1 mg/kg, 0.1 mg/kg, 0.01 mg/kg) intranasally on day 0. Onday 0 all mice were infected with Influenza virus strain PR8. On day 5post infection, mice were sacrificed, lungs isolated and viral loaddetermined by PCR. A dose response effect of sodium propionate could bedetected in the clearance of viral load in the lung tissue with a doseof 1 mg/kg showing the highest efficacy. These data show that a dose of1 mg/kg sodium propionate administered intranasally on day 0 seems to bean optimal dose in the protection against influenza virus infection whenadministered directly into the airways.

FIG. 6: show BALB/c mice, which were treated with saline or sodiumpropionate (100 mg/kg) intranasally on day 0 or day 1. On day 0 all micewere infected with Influenza virus strain PR8. On day 5 post infection,mice were sacrificed, lungs isolated and viral load determined by PCR.Efficacy in the reduction of viral load in the lung tissue on day 5could be detected in animals treated with sodium propionate (100 mg/kg)intranasally on day 0 and on animals treated on day 1. These data showthat a dose of 100 mg/kg sodium propionate administered intranasally onday 0 or day 1 exhibits efficacy in the protection against influenzavirus infection when administered directly into the airways and as suchthat a therapeutic treatment regime of sodium propionate per nasal showsefficacy in reducing viral load.

EXAMPLES Materials and Methods

The compounds of formula (I) can be manufactured by methods known in theart. Starting materials are either commercially available or can beprepared by methods known in the art.

Propionate:

Sodium propionate can be obtained commercially or manufactured bymethods known in the art.

Measurement of Antibodies: Fel d 1-ELISA.

-   1. Coat flat bottom 96-well plate (NUNC-Immuno MaxiSorp) with 5    μg/ml Fel d 1 final in 100 μl/well using Carbonate buffer pH 9.6    (see recipe below).-   2. Incubate overnight at 4° C.-   3. Wash 4× with PBS/0.05% tween.-   4. Block plate for 2 h at RT with 200 μl/well of PBS/0.05% Tween/1%    BSA.-   5. Make serial dilutions of your samples in PBS (usually 1:10,    1:100, 1:1000 and 1:10000 for sera and 1:10 and 1:100 for bronchial    alveolar lavage fluid (BALE)).-   6. Wash 4× with PBS/0.05% Tween,-   7. Add 100 μl/well of diluted samples (in duplicates).    Note: Keep some wells to do test have a background control=blank    (only PBS).-   8. Incubate 2 h at RT.-   9. Wash 4× with PBS/0.05% Tween.-   10. Add 100 of Alkaline Phosphatase (AP)-conjugated anti-mouse IgG1,    IgG2c, IgA or biotinylated anti-mouse IgE, all diluted at 1:1000 in    PBS/0.2% BSA.-   11. Incubate for 2 h at room temperature.-   12. Wash 4× with PBS/0.05% Tween the wells with biotinylated    anti-mouse IgE only and add 100 μl/well of AP-conjugated    streptavidin diluted at 1:1000 in PBS/0.2% BSA.-   13. Incubate 20 min at room temperature.-   14. Wash 4× with PBS/0.05% Tween.-   15. Dissolve 1 Alkaline Phosphatase Substrate Tablet (Sigma, cat. #    N2765-100TAB) into 20 ml of TM Buffer.-   16, Add 100 μl per well.-   17. Develop in the dark and read at 405 nm.

Carbonate Buffer recipe: 8.4 g NaHCO₃, 3.56 g Na₂CO₃ qsp 1 Liter withddH₂O. pH to 9.6 and store at 4° C.

TM Buffer recipe: 121.1 g Tris Base, 1 ml 0.3 M MgCl₂ qsp 1 Liter ddH₂O.pH to 9.8.

Cytokine and Chemokine Measurement:

Bronchial alveolar lavage fluid was measured for specific cytokinesutilizing a LegendPlex assay (Biolegend) following manufacturersinstructions.

Collection and Analysis of Bronchoalveolar Lavage (BAL) Cells.

BAL was performed by flushing the airways three times with 1 ml PBS.Total BAL cells were counted using a Coulter Counter (IG Instruments)and spun onto glass slides using a Cytospin 2 (Shandon SouthernProducts, Ltd.). Cells were then stained with Diff Quick staining set(Siemens-Dade Behring). Percentages of eosinophils, macrophages,lymphocytes and neutrophils were determined microscopically usingstandard morphological and cytochemical criteria.

Example 1 Propionate Intranasal Efficacy Study—Influenza

Female BALB/c mice were purchased from Charles River Laboratories at 8weeks of age. The mice were exposed to either 30 μl of sterile saline or30 μl of Sodium Propionate dissolved in saline (100 mg/kg dose)intranasally on day −3, −1 and 0. On day 0 mice were infected with 100PFU of Influenza strain PR8 in 30 μl of PBS solution. On day 5 postinfection, mice were sacrificed and lungs were removed and placed in Trireagent solution. Total RNA was purified from cells obtained from wholelung tissue using Tri reagent. Real time PCR was carried out accordingto manufacturers instructions using the quantifast SYBR green RT-PCR kit(Qiagen). The following primers influenza matrix protein primers wereused: forward 5′-GGA CTG CAG CGT AGA CGC TT-3′, reverse 5′-CAT CCT GTTGTA TAT GAG GCC CAT-3′. B-actin primers forward 5′-CCC TGA AGT ACC CCATTG AAC-3′, reverse 5′-CTT TTC ACG GTT GGC CTT AG-3′ as previouslydescribed van Elden, L. J., M. Nijhuis, P. Schipper, R. Schuurman, A. M.van Loon. 2001. Simultaneous detection of influenza viruses A and Busing real-time quantitative PCR. J. Clin. Microbial. 39: 196-200.Prophylactic treatment with sodium propionate administered intranasallyresulted in a markedly lower viral load in the lungs of mice, ascompared to mice treated with saline alone. These data show that sodiumpropionate exhibits efficacy in the protection against influenza virusinfection when administered directly into the airways (as shown in FIG.1).

Example 2 Propionate is Effective Against Metapneumonia Virus (MPV)

Female BALB/c mice (10 weeks old, Charles River Laboratories) were givenSodium Propionate (100 mg/kg) or saline intranasally in a volume of 30ul on day −1 and 0. On day 0 mice were infected with 1×10⁶ PFU ofmetapneumonia virus A1 6621 (MPV) in a volume of 100 ul.

On day 5 post infection, mice were sacrificed and lungs were removed andplaced in Tri reagent solution. Total RNA was purified from cellsobtained from whole lung tissue using Tri reagent. Real time PCR wascarried out according to manufacturers instructions using the quantifastSYBR green RT-PCR kit (Qiagen). The following primers MPV-specificprimers were used: forward 5′-GCC GTT AGC TTC AGT CAA TTC AA-3′, reverse5′-TCC AGC ATT GTC TGA AAA TTG C-3′. B-actin primers forward 5′-CCC TGAAGT ACC CCA TTG AAC-3′, reverse 5′-CTT TTC ACG GTT GGC CTT AG-3′. Thesedata show that sodium propionate exhibits efficacy in the protectionagainst MPV infection when administered directly into the airways (asshown in FIG. 2 and Table 1).

TABLE 1 Propionate exhibits efficacy in the protection against MPVinfection. Mouse Saline (Control) Na Propionate Number [β-actin/MPV Cqratio] [β-actin/MPV Cq ratio] 1 21000 17300 2 19700 16200 3 29900 145004 25100 12000 5 25200 18800 6 24300

Example 3 Propionate Intranasal Efficacy Study—HDM Asthma

Female BALB/c mice were purchased from Charles River Laboratories at 8weeks of age. On day −5 and −3 (pretreatment group), or day −5, −3, 0, 2and 4 (pretreatment and priming group), or day −5, −3, 0, 2, 4, 7, 9, 11(pretreatment, priming and challenge group) mice were exposed to sterilesaline or sodium propionate (100 mg/kg) intranasally in 15 μl ofsolution. On days 0, 2, 4, 7, 8 and 11 mice were exposed to 15 μg ofhouse dust mite extract (Greer) per nasal. On day 14, all mice weresacrificed and bronchoalveolar lavage (BAL) was performed with sterilePBS. The total number of macrophages, eosinophils, lymphocytes andneutrophils was determined by total and differential cell counts usingstandard morphological and cytochemical techniques. Specifically, totalcell count was performed using a coulter Z2® (Particle count and sizeanalyzer, Beckman coulter). Cytospin preparations of 50,000 cells wereperformed at 800 rpm for 5 min (Cytospin 3e, Thermo Shandon, Astmoor,United Kingdom). After cytocentrifugation, cells were stained usingDiff-Quick kit (IMEB, Chicago, Ill.), and differential cell countsobtained using standard morphological criteria to classify individualleukocyte populations. The data show that all treatment regimes resultedin statistically significant reductions in airway eosinophiliaindicative of a protective effect against the allergic response (asshown in FIGS. 3A-D).

Example 4 Efficacy of Short Chain Fatty Acids Against Influenza VirusInfection in Mice

Sodium propionate given into the airways of BALB/c mice is protectiveagainst influenza infection. Its effective range was shown to be in arange of between 100 mg/kg and 1 mg/kg.

4.1 Experiment 1:

Effectiveness of pretreatment of mice with sodium propionate i.n. (atindicated doses) on protection against influenza virus

4.1.1 Material and Methods 4.1.1.1 Number of Animals:

Four female BALB/c mice aged 8 weeks (purchased from Charles River) wereused per group.

4.1.1.2 Preparation of Dose Formulation:

Sodium propionate was dissolved in the balanced salt solution phosphatebuffered saline (PBS) at a concentration of either 40 mg/ml (for 100mg/kg dosing); 4.0 mg/ml (for 10 mg/kg dosing) or 0.4 mg/ml (for 1 mg/kgdosing). The solutions were filter-sterilized using 0.2 syringe filtersand stored at 4° C. PBS alone was used as a control.

4.1.1.3 Intranasal/Nasal Administration (i.n.):

On day 0 mice were anaesthetized by intraperitoneal (i.p.) injectionwith ketamine/xylazine and then 50 μl of the indicated solutions wereadministered utilizing a 200 μl pipette into the nostrils. The solutionswere all rapidly inhaled by the anaesthetized animals.

4.1.1.4 Influenza Infection:

On day 0, four hours following the administration of the propionatesolutions or control solution, mice were anaesthetized as describedbefore and infected with 100 PFU of Influenza A strain HK/PR8 per nasal.

4.1.1.5 Viral Titer Analysis:

The viral titers in the lungs were determined five days post infection(known to be the peak of the viral load in the lung from previousstudies). For this analysis, the mice were euthanized by i.p. injectionof 150 mg/kg, pentobarbital in 200 μl volume. Lungs were removed en blocunder sterile conditions, placed in Tri reagent and RNA was isolatedfollowing the manufacturers instructions (Molecular Research).

Real time PCR was carried out according to manufacturers instructionsusing the quantifast SYBR green RT-PCR kit (Qiagen). The followingprimers were used: GAPDH forward 5′-GGGTGTGAACCACGAGAAAT-3′; GAPDHreverse 5′-CCTTCCACAATGCCAAAGTT-3′; Influenza matrix protein forward5′-GGA CTG CAG CGT AGA CCC TT-3′, reverse 5′-CAT CCT GTT GTA TAT GAG GCCCAT-3′. Expression was determined either by using absolutequantification or by comparative delta threshold cycle method usingGAPDH as a comparator.

4.1.2 Result:

As shown in FIG. 4 and Table 2 below, mice treated with 1-100 mg/kg ofsodium propionate revealed reduced Flu titers compared to mice that onlyreceived saline (control). The lowest Flu titers could be observed inmice which received 1 mg/kg.

TABLE 2 Mice treated with propionate show reduced Flu titers compared tocontrol mice which received only saline. 100 mg/kg 10 mg/kg 1 mg/kgMouse Saline Na Propionate Na Propionate Na Propionate number (control)[flu/β-actin] [flu/β-actin] [flu/β-actin] 1 0.1739915 0.66134170.2044192 0.2110155 2 0.5965181 0.7202522 0.1213331 0.2010858 3 1.0018170.2205769 0.4034525 0.3507077 4 0.1876335 0.3315154 0.2733269 0.1830315

4.2 Experiment 2:

Intranasal dose titration of sodium propionate for treatment ofinfluenza infection

4.2.1 Material and Methods

The Material and Methods of Experiment 1 have been used, as described insection 4.1.1 above.

4.2.2 Result:

As depicted in FIG. 5 and Table 3 below, the dose titration ofintranasally administered sodium propionate against influenza infectionshows a trend towards efficacy from 100 mg/kg to 1 mg/kg and lack ofefficacy at a dose of 0.1 mg/kg or less. Mice which received 1 mg/kgsodium propionate showed the lowest Flu titer. From this results it canbe concluded, that the intranasal administration of sodium propionate ata dose of about 1 mg/kg may exhibit an ancillary effect if administeredtogether with a balanced saline solution for the treatment of commoncold and acute rhinitis.

TABLE 3 Dose titration of intranasally administered sodium propionateagainst influenza infection. 100 mg/kg 10 mg/kg 1 mg/kg 0.1 mg/kg 0.01mg/kg mouse Na Propionate Na Propionate NA Propionate NA Propionate NAPropionate number [delta Ct] [delta Ct] [delta Ct] [delta Ct] [delta Ct]1 0.2248162 0.05122631 0.00903277 0.01483913 0.01898603 2 0.22823350.1345269 0.07967126 0.2815218 0.2874926 3 0.02337933 0.11463940.01818559 0.3177531 0.05776232 4 0.01681005 0.03546309 0.027873560.082389 0.1427489 5 0.086991 0.2101459 0.468696

The working hypothesis for this ancillary effect is that sodiumpropionate supports a rebalancing of the local immune defense mechanismsin the nasal mucosa (NALT system) and facilitates on this way the mainefficacy of administration of the saline solution for the regularizationof the mucociliary defense system against pathogens. It could bedemonstrated that intranasal administered sodium propionate has aprotective efficacy against virus infection in mice at much lower dosescompared to the systemic administration (e.g. oral or intraperitonealadministration). Sodium propionate has in principle a therapeuticefficacy against influenza virus if it is administered systemically invery high doses of about 1 g/kg body weight. This dose corresponds to adaily dose of 60 g sodium propionate for a patient, which is practicallynot feasible. Furthermore interferences and disturbances in the regularmetabolic pathways should be expected as negative side effects.According to the results demonstrated above a dose of 1 mg/kg sodiumpropionate is an optimal dose for the intended treatment. This dosecorresponds to a daily dose of 60 mg per human being/consumer/patient.The solubility of sodium propionate in water is specified as 100 mg/mL.The maximal dosing volume for one pump action of the 3K-system is 140mg. Considering the solubility this amount contains 14 mg of sodiumpropionate which will be administered by one pump action. Conclusivelytwo pump action per nostril are necessary to administer 28 mg and ifboth nostrils are used the dose which is relevant for the ancillaryeffect of sodium propionate can be achieved.

4.2.3 Mechanism of Action

The mucociliary system in the nasal cavities is the first line ofdefence against pathogens like viruses or bacteria which are coming intothe human body by the upper airways. The first and mandatoryprerequisite for an effective functionality of this defence mechanism isa moist environment for the mucosa.

The second line of defense against the invasion of pathogens is thespecific local immune system in nasal respiratory mucosa which is partof the general lymphatic system (mucosa-associated lymphatic tissue;MALT) and specified as NALT (nose-associated lymphatic tissue).

In case of pathogen invasion, multiple immunocompetent cells immigrate,and increase the importance and functionality of this cellular defensemechanism. Up to now, no efficient treatment regimens exist, which aresupporting this local immune system in the respiratory mucosa withoutgenerating undesired systemic side effects. Thus, the present inventionprovides novel means and methods to modulate and induce the specificlocal immune system in nasal respiratory mucosa towards a Th1 cellresponse by transmucosal administration of SCFA, particularlyadministration of intranasal administration of propionic acid or apharmaceutically acceptable salt thereof.

4.3 Experiment 3:

Determination of efficacy dependent from timing of treatment

4.3.1 Material and Methods

The Material and Methods of Experiment 1 have been used, which are foundunder 4.1.1.

4.3.2 Result:

As shown in FIG. 6 and Table 4 below, sodium propionate can be givenbefore infection, the day of infection or the day after influenzainfection with similar efficacy. The treatment with sodium propionatei.n. (100 mg/kg) one day after influenza infection (Day +1) is still aseffective against controlling the virus as a treatment at the day ofinfection (Day 0).

TABLE 4 Timing of treatment of influenza infection. Saline Na PropionateNa Propionate mouse Day +1 Day +1 Day 0 number [flu/β-actin][flu/β-actin] [flu/β-actin] 1 0.316 0.277 0.244 2 0.3 0.312 0.334 30.311 0.217 0.303 4 0.357 0.176 0.154

1-61. (canceled)
 62. A method for the prevention, attenuation or treatment of a disease or disorder associated with a compromised Th1 immune response and/or an unwanted Th2 or Th2-like immune response comprising administering to a subject transmucosally a compound of formula (I)

wherein X is —O—, R is selected from the group consisting of methyl, ethyl, propyl, benzyl, nitrobenzyl, polyethylene glycol; R₁ selected from the group consisting of ethyl, hydroxyethyl; and R₂ is hydrogen; or pharmaceutically acceptable salts thereof.
 63. The method of claim 62, wherein the amount of T helper 2 (Th2) cell-derived cytokines is reduced in a subject treated with the compound of formula (I), particularly in the airways of said subject.
 64. The method of claim 62, wherein the circulating levels of immunogen-specific IgE are reduced in a subject treated with the compound of formula (I) and exposed to an immunogen.
 65. The method of claim 62, wherein the number of eosinophils is reduced in a subject treated with the compound of formula (I) and exposed to an immunogen, particularly in the airways of said subject.
 66. The method of claim 62, wherein said disease or disorder is: (a) an autoimmune disease selected from virus infection, asthma, rhinitis, dermatitis, drug reactions, esophageal and gastrointestinal allergy; (b) an allergic disease or disorder selected from the group consisting of allergic asthma, hay fever, drug allergies, allergic bronchopulmonary aspergillosis (ABPA), esophageal and a gastrointestinal allergy, pemphigus vulgaris, atopic dermatitis, onchocercal dermatitis, or a combination thereof; (c) an IgE-mediated disease or disorder selected from the group consisting of urticaria, eczema conjunctivitis, rhinorrhea, rhinitis, particularly allergic rhinitis, gastroenteritis, or a combination thereof; (d) an IgE-mediated disease or disorder selected from the group consisting of myeloma, multiple myeloma, Hodgkin's disease, Hyper-IgE syndrome, Wiskott-Aldrich syndrome, or a combination thereof; and (e) an eosinophilic disease or disorder selected from the group consisting of nodules, eosinophilia, eosinophilic rheumatism, dermatitis and swelling (NERDS).
 67. The method of claim 62, wherein the disease or disorder is selected from virus infection, asthma, chronic obstructive pulmonary disease and autoimmunity.
 68. The method of claim 67, wherein the disease or disorder is caused by virus infection selected from the group consisting of Influenza virus, respiratory syncytial virus, metapneumonia virus (MPV), human immunodeficiency virus, vaccinia virus, variola virus, dengue virus, coxsackie virus, hepatitis A virus, poliovirus, rhinovirus, Herpes simplex, type 1, Herpes simplex, type 2, Varicella-zoster virus, Epstein-barr virus, Human cytomegalovirus, Human herpesvirus, Hepatitis B virus, Hepatitis C virus, yellow fever virus, dengue virus, West Nile virus, Measles virus, Mumps virus, Parainfluenza virus, Human metapneumovirus, Human papillomavirus, Rabies virus, Rubella virus, Human bocavirus, and Parvovirus B19.
 69. The method of claim 68, wherein said viral infection is caused by an Influenza virus.
 70. The method of claim 62, wherein the compound is selected from the group consisting of: propionic acid, acetic acid, butyric acid, isobutyric acid, 2-hydroxyproirinic acid, dilactic acid, 2-benzyloxypropionic acid, 2-(p-nitrophenyl)-oxy-propionic acid, 3-hydroxypropionic acid, 2,3-dihydroxypropionic acid, methyl 3-hydroxypropionate, ethyl 3-hydroxypropionate, propyl 3-hydroxypropionate, benzyl 3-hydroxypropionate, para-nitrophenyl 3-hydroxypropionate, p-nitrobenzyl 3-hydroxypropionate, polyethylene glycol 3-hydroxypropionate, methyl propionate, ethyl propionate, propyl propionate, benzyl propionate, p-nitrophenyl propionate, p-nitrobenzyl propionate, 2-(4-Isobutylphenyl) propionic acid, lactic acid, citric acid, malic acid, malonic acid, succinic acid, and tartaric acid; or pharmaceutical acceptable salts thereof.
 71. The method of claim 70, wherein the compound of formula (I) is propionic acid or a pharmaceutically acceptable salt thereof.
 72. The method of claim 62, wherein the transmucosal administration is effected by intranasal, buccal, oral transmucosal, intratracheal, intraurinary tract, intravaginal, sublingual, intrabronchial, intrapulmonary or transdermal administration.
 73. The method of claim 72, wherein the transmucosal administration is effected by intranasal administration.
 74. The method of claim 73, wherein the compound of formula (I) is formulated as an aerosol; a dry powder or a liquid preparation.
 75. The method of claim 62, wherein the compound of formula (I) is administered to a subject before, on the day of, or one or more days after the viral infection has occurred to effectively reduce the viral titer in the treated subject.
 76. The method of claim 62, wherein the compound of formula (I) is provided as a composition comprising the compound of formula (I) or pharmaceutical acceptable salts thereof, in a pharmaceutically effective amount, together with a pharmaceutically acceptable carrier and/or a balanced salt solution.
 77. The method of claim 76, wherein the composition is formulated for use in intranasal administration.
 78. The method of claim 76, wherein the composition is formulated for use in sublingual administration.
 79. The method of claim 76, wherein the balanced salt solution is Locke-Ringer solution.
 80. The method of claim 76, wherein the composition is provided in a suitable delivery device, particularly a nasal insufflator device.
 81. A composition comprising a compound according to formula (I)

wherein X is —O—, R is selected from the group consisting of methyl, ethyl, propyl, benzyl, nitrobenzyl, polyethylene glycol; R₁ selected from the group consisting of ethyl, hydroxyethyl; and R₂ is hydrogen; or pharmaceutical acceptable salts thereof, in a pharmaceutically effective amount, together with a pharmaceutically acceptable carrier and/or a balanced salt solution formulated as an aerosol; a dry powder or a liquid preparation for intranasal administration.
 82. The composition of claim 81, wherein the compound of formula (I) is propionic acid.
 83. A pharmaceutical kit comprising the composition of claim 81 in a separate unit dosage form and a suitable delivery device, particularly a nasal insufflator device.
 84. The pharmaceutical kit of claim 83, wherein the compound of formula (I) is propionic acid. 